Consensus Builds on High-Dose Vitamin D for Breast Cancer Prevention–Despite IOM Report

2nd Wednesday, 2012  |   Breast Cancer  |  no comments

By Janet Gulland. Holistic primary Care. Vol. 11, No. 4. Winter, 2010

The role of vitamin D in cancer care was the subject of considerable attention at the recent Society for Integrative Oncology 7th annual assembly. Researchers and clinicians gathered at the meeting seemed to be moving toward a consensus that high-dose vitamin D supplementation has potential to markedly reduce risk of primary breast cancer as well as breast cancer recurrence, with minimal risk of toxicity.
Data presented at the meeting–held just two weeks before the Institute of Medicine’s Nov. 30 consensus statement dismissing the potential of vitamin D beyond bone health—indicate that women with serum levels under 20 ng/ml are at significantly increased risk of breast cancer, that raising levels to 50 ng/ml mitigates that risk, and that oral doses upwards of 10,000 IU/day are safe for women at risk of breast cancer.
While there are still many unanswered questions about the role of vitamin D in cancer prevention and treatment, speakers at the conference were largely in agreement that the standard Recommended Daily Allowance of 400 IU/day is grossly inadequate and has little scientific basis. The Institute of Medicine’s new recommendation of 600 IU for adults—including post-menopausal women won’t likely change anything.

A 40% Risk Reduction
Some of the strongest recent data comes from the Long Island Breast Cancer Study Project, which involved 1,026 women with breast cancer diagnosed between 1996 and 1997 compared with 1,075 matched controls. Vitamin D deficiency, defined as a serum level under 20 ng/ml, was common in both groups, but more prevalent among the women with cancer, reported Katherine Crew, MD, an epidemiologist at Columbia University College of Physicians & Surgeons, and lead investigator on the study.
Thirty-three percent of the cancer cohort was frankly deficient versus 28% of the cancer-free controls.
But the real message is in the analysis of odds ratios. The women who had blood levels of 40 ng/ml or greater had 40% lower odds of breast cancer versus those with serum levels of 20 ng/ml or lower. There was even a small 16% odds reduction among the women with serum levels of 20-29 ng/ml, which is low but not technically deficient. Dr. Crew noted that the data were adjusted for age, race, parity, family history of breast cancer, and other key variables (Crew KD, et al. Cancer Prev Res. 2009; 2(6): 598-604)
“Higher levels of 25-hydroxy-vitamin D confer lower risk of breast cancer. This was consistent for both estrogen receptor-positive (ER+) and negative (ER-) breast cancer, which is important because we really don’t have effective chemotherapy for ER- breast cancer,” Dr. Crew told attendees.

The study turned up several other interesting findings, including the fact that vitamin D deficiency correlates with obesity, which also increases cancer risk. The researchers found deficiencies in 36% of the women with body mass indices over 30, but only 23% of those with BMI’s under 25. The explanation is not yet clear, but Dr. Crew suggested that there may be a fat sequestration effect wherein vitamin D is being stored in adipose tissue, thus lowering serum levels in the obese women.

Sense in Supplementation
The Long Island data are compelling, but Dr. Crew urged caution in drawing definitive conclusions. “These are observational findings based on one measurement of serum vitamin D status; we don’t know from this study if raising the vitamin D level would lower breast cancer risk, and even if it does, we don’t know the best and safest method for doing this.”

Other studies, however, are pointing the way toward clear risk reduction strategies.
For example, the Women’s Health Initiative’s 2007 report, while showing no significant risk reduction from vitamin D at the standard 400 IU/d dose, did show a 20% reduction in breast cancer incidence among the women who reported taking additional vitamin D, on their own, beyond the “official” 400 IU dose. The biggest incidence reduction was for ER- cancers. Dr. Crew said the findings are definitely significant though they have been largely overlooked.
Also in 2007, Lappe and colleagues published a study of 1,179 post-menopausal women showing that those taking 1,100 IU/d of vitamin D plus calcium (1,500 mg/d) had far lower incidence of breast cancer versus those taking placebos (2% versus 6.8%). A third subgroup, taking calcium alone, also had fewer breast cancers but the incidence reduction was not as great (3.6% versus 6.8%) (Lappe et al. Am J Clin Nutr. 2007; 85(6):1586-91).
Looking at the best available data, it seems that breast cancer odds ratios begin to drop significantly as serum vitamin D levels get over 50 ng/ml. According to Garland and colleagues, you see a 50% risk reduction right around a serum level of 52 ng/ml (Garland et al. J Steroid Biochem Mol Biol. 2007; 103(3-5): 708-11). Progressive, nutrition-oriented oncologists agree that 40-60 ng/ml is the target range.

How Much?
So, how much vitamin D does a woman have to take to get up to the cancer-prevention range? At least 3,000-4,000 units per day, depending on the extent of the deficiency. This is almost an order of magnitude higher than the Institute of Medicine’s new RDA of 600 IU, but within range of the new Upper Limit.
What about toxicity? The most worrisome potential adverse effects of excessive vitamin D would be hypercalcemia, bone demineralization, nephrocalcinosis, and cardiac arrhythmias. However, these problems don’t really arise until serum levels get above 150 ng/ml, said Dr. Crew. Someone would have to take a lot of vitamin D over a long period to get the blood level up in that range.
Back in 2004, Vieth and colleagues studied daily doses of 10,000 IU for up to 5 months, and found no evidence of toxicity (Vieth et al. J Steroid Biochem Mol Biol. 2004; 89-90(1-5): 575-9).

Safe at 30,000 IU per Week
Dr. Crew’s group at Columbia is assessing the effect of cholecalciferol (vitamin D3) at high doses of 20,000 IU and 30,000 IU per week, in vitamin D deficient pre- and post-menopausal women at high breast cancer risk. The women will be treated for a full year. Breast-specific outcome measures include tissue changes on biopsy, imaging of breast fibrodensity, as well as urine and serum markers.
If looked at in terms of daily doses, these weekly dose levels—roughly 2,800 IU and 4,300 IU per day—are considerably higher than the IOM’s new recommendation of 600 IU per day. However, Dr. Crew said in an interview with Holistic Primary Care that they do fall close to the IOM’s new safe upper limits for women in this age bracket.
According to Julie Campbell, a research fellow who presented preliminary findings at the SIO conference, the study will ultimately involve 80 women in total. So far, 20 pre-menopausal and 14 post-menopausal women have completed the trial, with no evidence of any adverse effects at either dose level. “There have been no cases of hypercalcemia so far, and only one woman has show high urine calcium levels,” said Ms. Campbell.
She pointed out that that high-dose supplementation leads to rapid correction of deficiencies. Among the pre-menopausal women, mean levels were up in the 50-60 ng/ml range within 3 months, with the 30,000 IU weekly dose giving larger rises than the 20,000 IU weekly dose. It is important to note that even at these high doses, none of the subjects got up into the potentially toxic 150 ng/ml serum range.
The study is ongoing, and investigators have not yet completed analysis of vitamin D’s effects on breast tissue. However, the available data indicate that two of the 20 pre-menopausal women receiving 30,000 IU per week had a 15% reduction in fibrodensity, a surrogate marker for cancer risk.

“These are pilot data but they are compelling,” Ms. Campbell said. “High dose vitamin D supplementation can successfully raise serum levels to target range within a year, without significant toxicity. Based on imaging and biomarkers, there are possible preventive effects.”
Though the IOM report seems to dismiss the potential anti-cancer benefits of vitamin D supplementation, while raising a specter of alarm based on little evidence of actual toxicity incidence, the Columbia experience suggests little downside to supplementing in the range of 10,000-30,000 IU per week. The only major caveat being that one needs to watch calcium closely. Raising the serum vitamin D level will tend to increase calcium absorption, so if a patient is taking a lot of calcium the vitamin D boost could potentially increase risk of kidney stones.
The role of vitamin D in primary breast cancer prevention should become more clear on publication of a new Phase IIB intervention trial by the Southwest Oncology Group. The study involves 200 high-risk women randomized to placebo or 20,000 IU per week and followed for a year.

Improving Survival, Preventing Recurrence
There’s growing evidence that serum vitamin D level is inversely correlated with risk of recurrence in women who’ve already had breast cancer. Researchers in Toronto studied 512 women diagnosed with early-stage breast cancer from 1989-1996, and followed them for an average of nearly 12 years. The women had a mean vitamin D level of 23 ng/ml at baseline, with 37.5% in frank deficiency ( The women who were vitamin D deficient had a roughly two-fold increased risk of cancer recurrence and death at 12 years compared with those who had “sufficient” vitamin D levels (Goodwin et al. J Clin Oncol. 2009; 27(23):3757-63).
Dr. Crew said her team saw a similar effect in the Long Island study, with a near doubling in the adjusted hazard ratio of death within 8 years among the vitamin D deficient women compared with those who had blood levels over 30 ng/ml.
Interestingly, women in northern latitudes diagnosed with breast cancer in the Summer or Fall have statistically better survival rates compared with those diagnosed in the Winter or Spring. Further, breast cancer has a 25% higher mortality rate in the Northeastern US compared with the Southwest. While there are many potentially confounding variables in epidemiological findings like this, Dr. Crew said there could very well be a vitamin D effect in play.

The Sunshine Vitamin is clearly a subject of great interest to cancer researchers these days, and future studies should help clarify optimal treatment strategies.
The new IOM report states that for the general population there’s no strong evidence for pushing supplementation beyond the 600 IU range, a conclusion that many are questioning. For women at-risk of breast cancer, the available data suggest a conclusion that runs counter to the IOM’s recommendations.
It makes good sense to test vitamin D levels in all at-risk women, and to do whatever is possible to get serum levels into the 40-60 ng/ml range.

Immune Enhancement, Avoidance of Interactions Are Keys to Chemotherapy Support

2nd Wednesday, 2012  |   Others  |  no comments

By Janet Gulland. Holistic Primary Care. Vol. 12, No. 1. Spring, 2011

It is no secret that many people with cancer take nutraceuticals and botanical medicines in conjunction with conventional chemotherapy, in the hope of enhancing the therapeutic effect, minimizing side effects, and improving their odds of a long, relatively healthy life.
The impulses are certainly understandable, but the mixing of supplements and other natural products with anti-cancer pharmaceuticals raises concern about the potential for supplement-drug interactions.
Until recently, there’s been a void of good science about the ways in which commonly used supplements interact with common chemotherapeutic drugs. With the emergence of integrative oncology emerges as a clinical discipline, researchers have begun to turn serious attention to this issue.
There are essentially two types of interactions: those in which one substance speeds the metabolism and clearance of another, thus decreasing the latter’s efficacy; and those in which one substance inhibits the clearance of another, making it toxic. It all comes down to how various drugs, nutrients, and botanical compounds are processed by the liver.
Roughly 75% of all known drugs are metabolized through the cytochrome P450 class of enzymes, making this a key locus for research on interactions.

Filling a Data Void
Researchers at MD Anderson Cancer Center, Houston, are engaged in a wide-ranging pharmacologic assessment of roughly 30 commonly used natural products, and their potential for interaction with common chemo drugs. This line of work will be important for guiding clinical care of people with cancer.
“When they don’t have any data, oncologists tend to tell patients not to risk it with natural products,” said Judith A. Smith, Pharm, D, Director of Pharmacology Research at MD Anderson’s Department of Gynecologic Oncology. This may be prudent, but it can result in patients missing out on the benefits that some natural products might confer.
Though work in this field is still at an early stage, Dr. Smith told Holistic Primary Care that her team has already identified a couple of nutraceuticals & natural products that pose little risk of interaction. They’ve also hit on one that should definitely be avoided.
Her group recently published a paper in the Journal of the Society for Integrative Oncology, on the interaction potential of AHCC (active hexose correlated compound), an extract obtained from a hybridization of several species of medicinal mushrooms. AHCC is supported as a cancer care adjunct by over 25 studies, and has been shown to decrease side effects of chemotherapy — including hair loss and bone marrow suppression.
In Japan, where AHCC was developed, it is often used in conventional practice, and it has attracted the interest of several prominent American oncologists.

AHCC: Little Risk of Interaction
Dr. Smith’s team conducted two studies: an in vitro metabolism study, to determine whether AHCC can inhibit P-450 detox pathways (i.e. if it might increase a drug’s toxicity), and an ex vivo human liver cell induction study, to evaluate whether it induces P-450 activity (i.e. if might reduce a drug’s efficacy).
The in vitro work indicates that AHCC does not inhibit the major P450 detoxification pathways, meaning it will not delay breakdown of most chemo drugs. “AHCC is unlikely to result in increased toxicity when used in combination with chemotherapy or supportive therapies such as anti-nausea medications or antidepressants.”
The ex vivo study indicated that AHCC does increase CYP450 2D6 activity. Therefore, it may have the potential to modulate the effect of drugs metabolized through that pathway. Fortunately, this is not a predominant pathway for metabolism of commonly used chemo agents, with the exception of doxorubicin and tamoxifen.
Tamoxifen must be metabolized by the 26D pathway to be converted to its active form, so induction of 26D might increase the effect of the drug. There are some case studies suggesting this does occur, though the interaction is not well understood. It is also possible that AHCC’s induction of 26D would increase tamoxifen toxicity, though this has not been observed. Until more is known, it is wise to be cautious in combining AHCC with tamoxifen. But since most other chemo drugs are not metabolized via 26D, there is little risk of interactions.
Among the other compounds Dr. Smith’s group has studied, L-glutamine is the only other so far that shares AHCC’s low potential for interactions. Some clinicians—and many cancer patients—believe L-glutamine supplementation bolsters immune function and diminishes mucosal injury from radiotherapy.
Noni juice, popular among cancer patients and promoted for immune strengthening, is a must-to-avoid with chemotherapy, said Dr. Smith. The foul-smelling, anthraquinone-rich juice from this Polynesian fruit is a powerful inducer of CYP450 enzymes.

Reducing Toxicity, Improving Lives
Lise Alschuler, ND, FABNO, an integrative oncologist in Bedford, NH, said it is important to understand and to respect the motives that drive cancer patients to augment allopathic cancer treatments with natural products.
“The prospect of having cancer invokes fear of pain, suffering and death. The treatments are, for many, as terrifying as the disease itself. Chemotherapy, the mainstay of conventional treatment, is perhaps the most feared of all. Nausea, diarrhea and/or constipation, mouth sores, fatigue, numbness and tingling of the extremities are common and sometimes severe. The need for additional therapies that will reduce the toxicity of chemotherapy is great.”
Dr. Alschuler, is co-author, with Karolyn Gazella, of The Definitive Guide to Cancer: An Integrated Approach to Prevention, Treatment, and Healing, now in it’s 3rd edition. Herself a breast cancer survivor–or “thriver” as she prefers it—Dr. Alschuler is particularly enthusiastic about AHCC’s potential.
“What makes it so exciting is its ability to improve both duration and quality of life. Two studies of patients with highly incurable primary liver cancer have shown that the individuals given AHCC experienced a significant prolongation of life as well as dramatic improvement in their quality of life.”
In these trials, AHCC reduced side effects while enhancing the tumor killing, translating into higher quality of life and increased survival times (Cowawintaweewat S, et al. Asian Pacific J Allergy Immunology. 2006;24:33-45. Gao Y, et al. Cancer Immunol Immunother. 2006; 55:1258-1266).

AHCC & the Immune System
One reason cancer cells are so dangerous is that they directly suppress immune function. Specifically, they suppress dendritic cells, the roving “eyes” of the immune system. Normally, when these cells encounter a cancerous or otherwise aberrant cell, they send out chemical signals (namely IL-12) that activate cytotoxic T cells and natural killer (NK) cells. Inhibition of dendritic cell signaling effectively disarms this entire branch of the immune system.
Chemotherapy can cause further damage because it can be very damaging to the stem cells in the bone marrow.
In a sense, the immune systems of people getting chemotherapy are slammed from both sides: the cancer itself blinds T cells and NK cells, and the drug-induced myelosuppression diminishes immune cell counts. Reversing and restoring suppressed immune function is an essential aspect of cancer care.
AHCC increases the number of dendritic cells and their ability to stimulate the rest of the immune system. It increases production of IL-12 and IFN-?.
In addition, AHCC specifically increases the activity of NK cells in cancer patients. “The combined effect is to unchain the immune system and to allow it to respond to, and destroy, cancerous cells,” Dr. Alschuler said. These immune-mediated anti-tumor effects have been demonstrated against melanoma and lymphoma cancer cells in tumor-bearing rodents.

The immune enhancing effect of AHCC is reason enough to consider it for patients needing immunosuppressive chemotherapy. It is particularly helpful in conjunction with cisplatin, one of the most common drugs for solid tumors. Cisplatin causes nausea, kidney damage, nerve damage, hearing loss, and overall malaise, making treatment quite distressing for patients. The side-effect burden sometimes limits the dose and duration, thereby decreasing efficacy.
Researchers in Japan have reported some preliminary findings that further support the syngergistic role of AHCC and many other chemotherapy agents including 5-fluorouracil, paclitaxel (Taxol), cyclophosphamide (cytoxan), 6-mercaptopurine (Purinethol), methotrexate, and cytosine arabinoside (Ara-C).
Human studies are bearing out the expectations set by the animal trials. Dr. Reiki Ishizuka of the Tajima Clinic in Sapporo, has reported on increased survival and improved quality of life in patients with lung, breast and colon cancers who were taking AHCC along with their conventional chemotherapy treatments. Those taking AHCC had improved immune function. Although these findings are preliminary, there is a growing body of evidence to support the use of AHCC along with chemotherapy – to improve its benefits and to reduce its side effects.

Anti-cancer effect of polysaccharides isolated from higher basidiomycetes mushrooms

AS Daba, OU Ezeronye. African Journal of Biotechnology Vol. 2 (12), pp. 672-678, December 2003
Anti-tumor activity of mushroom fruit bodies and mycelial extracts evaluated using different cancer cell lines. These polysaccharide extracts showed potent antitumor activity against sarcoma 180, mammary adenocarcinoma 755, leukemia L-1210 and a host of other tumors. The antitumor activity was mainly due to indirect host mediated immunotherapeutic effect. These studies are still in progress in many laboratories and the role of the polysaccharides as immunopotentiators is especially under intense debate. The purpose of the present review is to summarize the available information in this area and to indicate the present status of the research.

Active Hemicellulose Compound (AHCC) Enhances NK Cell Activity of Aged Mice in Vivo

Active Hemicellulose Compound (AHCC) is hemicellulose which originated from rice and is biologically modified using carbohydrase separated from Lentinus Edodes to increase its immunomodulatory function. In the present investigation, we evaluated the ability of AHCC to stimulate in vivo NK cytotoxic reactivity. Old C57BL/6 mice were injected i.p. daily at a concentration of 30 mg/kg/day. At 2, 5 and 14 days at post treatment, peritoneal erudite and apleen were examined for tissue cellularity and NK activity using 4-hr. Cr-release assay against YAC-1 tumor cells. The results demonstrate that; 1) AHCC generated peritoneal cytotoxic cells having the characteristics of NK cells with high levels of granularity. The induction was observed as early as 2 days, (750-900% of control) and maintained at high levels with continuous injections, 2) Peritoneal macrophage did not exhibit antitumor activity nor act as accessory cells for NK cells, 3) No significant induction of splenic NK cell activity, and 4) AHCC treated mice induced a significant increase in peritoneal (300-500%) and splenic cellularity (150-190%), suggesting that AHCC acts a mitogen factor in vivo. AHCC could be considered as a potent biological response modifier and its anti-cancer activity may be through post NK immunomodulation.
M. Ghoneum, Y. Ninomiya, M. Torabi, G. Gill and A. Wojani. C.

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.

1st Tuesday, 2012  |   Others  |  no comments

There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for approximately 10(6) single-nucleotide polymorphisms. We found that pancreatic cancers contain an average

of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors’ transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.

Signaling pathways and processes. (A) The 12 pathways and processes whose component genes were genetically altered in most pancreatic cancers. (B and C) Two pancreatic cancers (Pa14C and Pa10X) and the specific genes that are mutated in them. The positions around the circles in (B) and (C) correspond to the pathways and processes in (A). Several pathway components overlapped, as illustrated by the BMPR2 mutation that presumably disrupted both the SMAD4 and Hedgehog signaling pathways in Pa10X. Additionally, not all 12 processes and pathways were altered in every pancreatic cancer, as exemplified by the fact that no mutations known to affect DNA damage control were observed in Pa10X. N.O. indicates not observed.
Jones S, Zhang X, Parsons DW, Lin JC, et al. Science. 2008 Sep 26;321(5897):1801-6. Epub 2008 Sep 4.

Breast Cancer

1st Tuesday, 2012  |   Breast Cancer  |  1 comment

Eun Myoung Shin and Alan Prem Kumar. Innovation Journal 2012

Breast cancer is a cancer that starts in the tissue of the breast. There are two main types of breast cancer based on which part of breast tissue becomes cancerous (Figure 1). Ductal carcinoma starts in the tubes that move milk from the breast to the nipple. Most breast cancers are of this type. Lobular carcinoma starts in the parts of the breast that produces milk. In rare cases, breast cancer can starts in other areas of the breast. Men can get breast cancer though women are 100 times more likely to get breast cancer than men. Breast cancer is a complex and heterogeneous disease whose evolution is difficult to predict. Incidence rates of breast cancer have been increasing throughout the world. Breast cancer ranked the fifth, after lung, stomach, liver, and colon cancers, causing 460,000 deaths in 2008 according to World Health Organization Medica Center “Cancer” 2011 [1].

Cancer risk varies geographically and across ethnic groups that can be monitored in cancer control to respond to observed trends as well as ensure appropriate health care. According to a study reviewing 37 previous studies published between 1990 and April 2010 focusing on cancer in adult migrants from non-western countries, living in the industrialized countries of the European Union revealed that migrants from non-western countries were more prone to cancers that are related to infections experienced in early life, such as liver, cervical and stomach cancer. In contrast, migrants of non-western origin were less likely to suffer from cancers related to a western lifestyle, such as colorectal, breast and prostate cancer [2].

As Asian countries become increasingly westernized, incidence rate will increase for many cancers. Presently, breast cancer incidence rate is considerably lower than in Western countries, however, breast cancer risk has been ever increasing in most Asian countries. The age-standardized incidence rates of breast cancer had been increasing from 32.5 per 100,000 in 1983 to 35.0 per 100,000 in 2004 and further increased to 45.9 per 100,000 in Fig.1. Breast anatomy.2008[1]. Rapid urbanization, improvement in socio-economic status of women, and adaption of a western lifestyle can be possible explanations. In female, incidence of breast cancer ranked first in Taiwan, China, Singapore, Japan and India with the highest incidence (53.7 per 100,000) of breast cancers is in Manila, Philippines [1].

There are differences in incidence rates and trends between Caucasians and Asian populations suggesting further detailed research in enlightening the epidemiology of breast cancer in Asians be presented [3]. In Asian female, the incidence rates plateau in the middle age and declined in the older age with the mortality rates consistently increasing with age. The patterns of age-specific mortality during the last three decades in Hong Kong and Singapore gradually increases with age, while Japan, Korea and Taiwan showed rather flat or declining after age 50. Mortality rates by age group showed that for the woman aged 35-49 and 50-69 years, the rate has been increasing significantly in recent years in Japan, Korea, and Taiwan but decreasing in Hong Kong and Singapore [1, 4].

Despite the increasing incidence of and mortality from breast cancer, Asian women in the United States of America report consistently low rates of mammography screening. A number of health beliefs and sociodemographic characteristics have been associated with mammogram participation among these women. A cancer incidence and survival in Asian Indian-American patient study showed that the median age at diagnosis was 52 (range 25-79) and the median tumor size was 1.5 cm (range 0.2-4.5 cm). Differing from their Caucasian counterparts, Asian Indian-American women were more likely to present with palpable masses and at a younger age. This may indicate a social or cultural barrier to routine screening mammograms and possibly a biologically more aggressive tumor [5].

Breast cancer can be defined at the clinical, histological, cellular and molecular levels. In order to understand and refine the breast cancer taxonomy, from the initial histological features such as tumor size, tumor grade, lymph node status and the presence of predicative markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status to a further sophisticated classification of luminal A, luminal B, HER-2 positive, basal-like and the normal subtypes have been established to facilitate cancer treatments. Over the decade, this profiling has contributed significantly to our understanding of this heterogeneity at the molecular level. Gene expression profiling studies have further identified several breast cancer subtypes associated with markedly different clinical outcomes. Currently, hormonal therapy is prescribed to patients with ER positive breast cancer. In principle, the estrogen antagonist Tamoxifen is used to block the effects of estrogen, which can help ER positive breast cancer cells survive and grow. Another class of hormonal therapy medicines called aromatase inhibitor, such as exemestane (Aromasin) blocks estrogen from being made. For the HER2 positive breast cancer patients, HER2 targeted treatment trastuzumab (Herceptin) can be used. On the other hand, chemotheraphy is currently the mainstay of systemic treatment for ER negative, progesterone negative and HER2 negative subtypes (triple negative subtype) of breast cancer due to hormonal and HER2-directed therapies are not effective. The overall poor prognosis of patients with triple negative breast cancer and/or basal-like breast cancer and their tendency to relapse with distant metastases indicate a definite need for effective systemic therapies for this disease. Chemotherapy for the treatment triple negative breast cancer and basal like breast cancer have been trying diversified strategies so far. Several PARP inhibitors are in phase II/III development and angiogenesis inhibitor bevacizumab, which targets VEGF, is currently under investigation both in triple negative breast cancer patients and in patients with metastatic breast cancer in combination with a taxane. The anti-diabetic drug metformin has been shown to inhibit proliferation and induce apoptosis of triple negative breast cancer in preclinical studies, in addition to inducing other beneficial biological changes in breast cancer of various types. Clinical trials for EGFR inhibitors are also being evaluated in triple negative breast cancer patients. Tyrosine kinase c-src is another therapeutic target in breast cancer since c-src is associated with increased motility and invasiveness in breast cancer [6]. Encouraging results have been reported, yet preclinical and clinical trials are still on the process and there are little prospective data at current time.

Triple negative breast cancers occurred 2-3 times more frequently in African American patients (up to 47% of breast cancers), the percentage of triple negative breast cancers was 55% in West-African patients, 31% in Korean patients, 18% in Chinese patients and 16% in Taiwanese patients, and 8% in Japanese patients[6]. In Asian countries, Korea showed the most rapid increases in breast cancer mortality for all age group with the highest triple negative rate in Asia. A medical record review study of 683 patients consisted of 136 triple negative breast cancer and 529 non-triple negative breast cancer cases showed that triple negative breast cancer correlated with younger age (< 35 years), and higher histologic and nuclear grade in Korean cohort. It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression, positive for the epidermal growth factor receptor, and a high level of p53 and Ki67 expression. Relapse free survival was significantly shorter among patients with triple negative breast cancer compared with those with non-triple negative breast cancer [7]. Apart from that patients with triple negative breast cancer were more likely to develop distant metastasis earlier, and also evidenced poor overall survival. Triple receptor status may be employed as a prognostic marker for breast cancer patients with brain metastases [8]. Similarly, basal-like triple negative breast cancers are associated with adverse clinicopathologic parameters, and that individual biologic markers of CK17, CD117, and SMA have prognostic implications on survival. Possibilities exist for future targeted therapy for this challenging group of breast cancers [9]. In summary, however, according to a review study of 1018 breast cancer patients in Canada, the differences in survival and prognostic factors between patients with triple-negative breast cancer and those with non-triple negative breast cancer was insignificant. The significant predictors of survival in the adjusted analysis were age, stage of cancer, and size of cancer, indicating that presenting tumor size at diagnose is the most important prognostic factor in triple negative breast cancer. Investigations into unique screening methods to identify these tumors at an earlier stage and to prevent advanced-stage cancer in this patient subpopulation are necessary. Late stage at diagnosis was largely responsible for low survival. In Western countries, mortality started to decline due in part to birth cohort effects for women born from the end of 19th century to the mid-1920s and the decline is further expected to continue in this decade due to the long term result of both mammography screening and improved medical intervention [4]. Medical services for breast cancer patient management have reached the quality standards in the guidelines in Asian countries since 1990s. Taiwan started a stratified breast screening program in 1995. Singapore, Japan and Korea organized breast cancer screening program in 2002 that combines mammography with clinical breast examination. European countries which started breast screening program in early 1990s have experienced decline in the breast cancer mortality rate [4]. Early detection and treatment improvement will continue to reduce the mortality rates as observed in Western countries. However predominant early onset and aggressive ER-negative breast cancers may still partially account for the high breast cancer mortality in Asian countries.

Greco-Arab and Islamic Herbal-Derived Anticancer Modalities: From Tradition to Molecular Mechanisms

1st Tuesday, 2012  |   Others  |  no comments

Hilal Zaid, Michael Silbermann, Eran Ben-Arye, and Bashar Saad

Evid Based Complement Alternat Med. 2012; 2012: 349040.
Published online 2011 November 22. doi: 10.1155/2012/349040

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence of cancer is increasing in the developed countries and even more so in developing countries parallel to the increase in life expectancy. In recent years, clinicians and researchers advocate the need to include supportive and palliative care since the establishment of the diagnosis and throughout the duration of treatment, with the goal of improving patients’ quality of life. This patient-centered approach in supportive care is also shared by various traditional and complementary medicine approaches. Traditional Arab-Islamic medicine offers a variety of therapeutic modalities that include herbal, nutritional, and spiritual approaches. Physicians and scholars, such as Avicenna (980–1037), Rhazes (965–915), Al Zahrawi (936–1013), and Ibn al Nafis (1218–1288) referred to cancer etiology in various medicinal texts and suggested both preventive and therapeutic remedies to alleviate suffering. This review presents research data related to the anticancer activities of herbs used in Arab-Islamic medicine and allude to their potential role in improving the quality of life of cancer patients.

1. Introduction
In recent years, traditional Arab-Islamic herbal medicine has been gaining interest in the scientific community, and more specifically, regarding cancer treatment [1–3]. This school of medicine, often referred to as Greco-Arab medicine, is still influential in Arab and Islamic societies, especially throughout the Mediterranean region. Throughout Muslim history, Greco-Arab and Islamic herbal medicine were the first choice of treatment for ailments involving infertility, epilepsy, cancer, psychosomatic troubles, and depression. Arab and Muslim physicians were among the first to use scientific methods in the field of medicine, including the introduction of quantity measurements, animal testing, and clinical trials. Hospitals in the Arab-Islamic world featured drug tests, drug purity regulations, and competency tests for physicians. The earliest known tests related to public health were carried out by Rhazes (865–925), searching for the most hygienic place to build a hospital. To that purpose, he placed pieces of meat throughout Baghdad and subsequently built a hospital at the site where the meat decomposition was the least. In his Comprehensive Book of Medicine, Rhazes documented his own clinical cases and provided very useful documentation of various diseases. He also introduced urinalysis and stool tests. Avicenna (980–1037), who introduced quantity measurements in experimental medicine, discovered the contagious nature of diseases, introduced clinical trials, risk factor analysis, and the idea of a syndrome in the diagnosis of complex clinical entities. His book, The Canon of Medicine, was the first to deal with evidence-based medicine, randomized controlled trials, and efficacy tests.
Concerning medical documentation, the first documented evidence for a peer review publication was published by Ishaq bin Ali al-Rahwi (854–931). In his work, the Ethics of the Physician, he stated that a physician must always document in duplicate the patient’s records. When the patient was healed or died, the physician’s records were examined by a local medical council, comprising of other physicians, in order to decide as to whether the treatment met the required standards of medical care.
Cancer is a leading cause of mortality, and it strikes more than one-third of the world’s population and it’s the cause of more than 20% of all deaths [4]. Among the causes for cancer are tobacco smoke, viral infection, chemicals, radiation, environmental factors, and dietary factors. Contemporary physicians and biomedical researchers advocate the need for a comprehensive cancer treatment including supportive and palliative care. This patient-centered approach is based, in part, on the increased awareness of the role of traditional and complementary medicine in supportive care aimed at improving patients’ quality of life. This review aims at elucidating Arab and Islamic medicines and their involvement in approaching issues associated with cancer diagnosis and treatment, while reviewing the potential role of herbs in contemporary cancer care.

2. Relevance of Arab and Islamic Medicine on Cancer Care in the Middle East
In early 2011, Ben-Arye and his colleagues from six Middle-Eastern countries identified 143 articles on complementary and traditional medicine that had been published in 12 Middle-Eastern countries in relation to cancer care [5]. In studies performed in Turkey and Israel, about half of the patients diagnosed with cancer reported use of complementary and alternative medicine (CAM) [6], even during chemotherapy treatment [7]. These findings are comparable with other reports in the West [8]. Herbal medicine is the leading modality used by patients with cancer in the Middle East (e.g., 35% of cancer patients using CAM in Jordan) [9] along with spiritual practices that are also prevalent (e.g., 75% of CAM users in Iranian study) [10]. CAM use is also popular among patients with pediatric [11], gynecological [12], and hematological [13] malignancies and among patients with an advanced disease [14]. Ben-Arye and colleagues reported on 59 articles published in the Middle East in relation to cancer-related herbal research including ethnobotanical surveys and reviews (7 articles), in vitro studies (33 articles), animal studies (8 articles), and clinical studies (11 articles) [15].

3. Cancer in Greco-Arab and Islamic Medicine
Roman physicians, for example, Galen (129–199), were already acquainted with tumors as clinical entities while adopting Hippocrates’ (470–370 BC) basic theory of cancer being an excess of black bile. In the golden Islamic-Arab era, classic texts, including those of Galen, were translated into Arabic and thereby influenced physicians in the Arab-Islamic world. During the Golden Arab-Islamic civilization (7th to 14th century), Arab and Muslim physicians studied cancer and applied various medicines and surgical means for its treatment. In the medicinal texts of Rhazes, Avicenna, and Abulcasis, the authors distinguish clearly between the varieties of cancer types in relation to specific organs such as, eye, nasal, tongue, stomach (gastric), liver, bladder, kidney, testis, breast, spleen, and nerve tumors. Kidney cancer was first mentioned by Al Zahrawi (Abulcasis 936–1013) who was the first to differentiate between acute inflammation of the kidney and kidney cancer. Both Rhazes and Avicenna described cancer as a disease which is difficult to treat.
Rhazes, Abulcasis, and Avicenna all realized that the prospects of curing cancer are prognostically improved if the cancer is detected at an early stage [16, 17]. Hence, the first goal of treatment would be controlling the tumor’s growth. They recommended surgical removal if the tumor was small and accessible, and not close to vital organs. Avicenna (980–1037), the most influential of all Islamic philosopher scientists, suggested “When cancer starts, it may be possible to keep it as it is, so that it will not increase and keep it non-ulcerated. It may happen sometimes that the stating cancer may be cured. But when it is advanced, verily will not” [16, 17]. In his book, Canon, Avicenna described four ways to treat cancer: (a) total arrest, which was regarded as difficult; (b) preventing progress; (c) preventing ulceration; (d) treatment of the ulceration. He empathized that medications per se would not be of great value since strong medications increase “cancer evil”. In addition, “one should avoid irritant medications. And for this, good medications are: pure minerals like washed pure tutty mixed with oils like rose oil and the oil of yellow gillyflower mixed with it” [16]. Avicenna also described one of the very early surgical approaches for cancer treatment, as he noted “the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor … so that nothing of these will be left” [16, 17]. He also recommended the “use of cauterization for the area being treated if necessary.” One mode of treatment which he discovered was the “Hindiba” (The plant Chicorium intybus), which Ibn al-Baitar later on identified as having anticancer properties and which could also be used for other tumors and neoplastic disorders [2, 18–20]. Avicenna had also stated that “it (cancer) can be reached by controlling the material, improving the diet and reinforcing the involved organ by the known effective medicines, and by using mineral smears like those containing millstone dust and whet-stone dust and from smears taken from a mixture between the stone pounder for aromatics and black head stone moisturized with rose oil and coriander water…”.

4. Cancer Prevention and Treatment in Greco-Arab and Islamic Medicine
Based on recommendations of Rhazes and Avicenna, patients in general were treated through a scheme starting with physiotherapy and diet; if this failed, drugs were used. Rhazes treatment scheme started with diet therapy, he noted that “if the physician is able to treat with foodstuffs, not medication, then he has succeeded. If, however, he must use medications, then it should be simple remedies and not compound ones”. Drugs were divided into simple and compound drugs. Physicians were aware of the interaction between drugs, thus, they used simple drugs first. If these failed, compound drugs consisting of two or more compounds were used. If these conservative measures failed, surgery was undertaken.

4.1. Diet-Based Prevention and Therapy
Food was a substantial part of pre-Islamic medicine as well as in other traditional medicines, for example, Greek, Persian, Ayurvedic, and Chinese. Diet is a matter of faith in Islam and plays an important role in maintaining a healthy body, soul, and spirit. Muslims are commanded to follow a set of dietary laws outlined in the Holy Qur’an, where almost everything is permitted, except what Allah specifically prohibited. Later on, when the Islamic empire covered all of Arabia, half of Byzantine Asia, all of Persia, Egypt, the Maghreb (North Africa), and Spain, Arabs and Muslims not only conquered new lands, but also became exposed to foreign and multinational culinary heritages. Great developments in scientific fields, the establishment of “modern” hospitals, and growing socioeconomic conditions of Islamic empire increased the awareness of the relationship between food and health. During this period a type of Islamic food therapy was developed that was a blend of Qur’anic teaching and Greek medicine.

According to a Hadith (saying) of the Prophet, Peace Be Upon Him (PBUH) “The stomach is the central basin of the body, and the veins are connected to it. When the stomach is healthy, it passes on its condition to veins, and in turn the veins will circulate the same and when the stomach is putrescence, the veins will absorb such putrescence and issue the same”. Indeed, the Prophet used to recommend food for ailments even more than he prescribed herbs or medicines. The impact of diet and herbs for the well being of people was also acknowledged in the Holy Qur’an which mentioned beneficial effects of several plants and animal products on nutritional health. Among these are grapes, citrus, melon, squash, figs, dates, honey, olive oil, and black seeds. For example, figs (Ficus carica) are mentioned by the Prophet (PBUH) who state that “If I had to mention a fruit that descended from paradise I would say this is it because the paradisiacal fruits do not have pits…eat from these fruits for they prevent hemorrhoids, prevent piles and help gout.” [21]. Indeed, ethnobotanical research suggests that figs are used to treat malignant and inflammatory diseases [22]. The Prophet (PBUH) also recommended the use of olive oil, by stating “Eat olive oil and massage it over your bodies since it is a holy (Mubarak) tree”. Dates were mentioned in twenty places in the Qur’an, as the Prophet (PBUH) was reported to have said: “if anyone of you is fasting, let him break his fast with dates. In case he does not have them, then with water. Verily water is a purifier” [21].
Greco-Arab and Islamic scholars, such as Avicenna, Rhazes, and Abulcasis discussed the effect of diet on cancer development and progression. While alluding to cancer prevention Avicenna quoted “As to preventing its (cancer) progress, it can be achieved by … improving the diet and reinforcing the involved organ by the known effective medications.” This ancient attribution of the role of nutrition in cancer has been acknowledged extensively in the scientific literature involving carcinogenesis [23] and the interrelation between cancer incidence and recurrence and nutrition and lifestyle (e.g., obesity as a cancer risk factor [24, 25]).

4.2. Mediterranean Diet
During the last half-century, epidemiological studies have consistently shown that there are clear significant positive associations between intake of fruits and vegetables and reduced rate of heart diseases mortality, common cancers, and other degenerative diseases as well as ageing. This is attributed to the fact that these foods may provide an optimal mix of dietary fiber, natural antioxidants, and other biotic compounds. Various substances in the food can control the physiological functions of the body and modulating immune responses. Immune functions are indispensable for defending the body against attack by pathogens or cancer cells and thus play a pivotal role in the maintenance of health. However, the immune functions are disturbed by malnutrition, aging, physical and mental stress, or undesirable lifestyle. Therefore, the ingestion of foods with immune-modulating activities is considered an efficient way to prevent immune functions from declining and reduce the risk of infection or cancer.
Traditional Mediterranean diet includes a significantly large amount and variety of plant foods, for example, fruits, vegetables, wild edible plants, breads, seeds, nuts, and olive oil. Therefore, it guarantees an adequate intake of carotenoids, vitamin C, tocopherols, ?-linolenic acid, various important minerals, and several possibly beneficial nonnutrient substances such as polyphenols and anthocyanins and dietary fiber [26, 27].

4.3. Edible Wild Plants
Wild edible plants are commonly consumed in the eastern region of the Mediterranean. Wild edible herbs have always been a main part of traditional diets and were known for their health qualities among local communities and indigenous people long before their nutritious, protective, and therapeutic effects were proved by scientific research. A high percentage of individuals collect wild edible plants and consume them as part of traditional food habits. Traditional food habits have been characterized by dietary diversity and have been associated with low health risks. Wild edible plants have been identified as main components of these diets and as important contributors to their health-protective properties. Many wild species are collected from the surrounding environment and consumed as part of local diets, especially in times of shortage. Various wild greens contain high nutritional values with relatively low energy. Compared with commonly eaten vegetables, they provide the diet with greater amounts of minerals. Additionally, their antioxidant property, mainly from phytochemicals, was found to be two to three times higher than that of common vegetables [26].

4.4. Herbal-Based Prevention and Therapy
There is compelling evidence from epidemiological and experimental studies that highlight the importance of phytochemicals isolated from traditional medicinal plants to prevent/reduce some types of cancer and inhibit the development and spread of tumors in test animals. The term phytochemical refers to any herbal-based molecule, but in the field of diet and cancer this term is usually applied to nutritive and nonnutritive compounds that occur naturally in fruits and vegetables. More than 25% of drugs used during the last 20 years are directly derived from plants, while the other 25% are chemically altered natural products. Still, only 5–15% of the approximately 260,000 higher plants have ever been investigated for bioactive compounds. The advantage of using such compounds for cancer treatment is their relatively low/non-toxic nature [28, 29]. An ideal phytochemical is one that possesses antitumor properties with minimal side effects and has a defined mechanism of action. Some phytochemicals are likely to possess anticancer effects (Table 1). According to recent surveys, many cancer patients use complementary and alternative medicines, including phytochemicals in addition to, or following the failure of standard cancer therapy. A diet rich in fruits and vegetables has long been suggested to correlate with reduced risk of certain epithelial malignancies, including cancers in the lung, colon, prostate, oral cavity, and breast [28, 30]. Also, the cancer prevention potential of Mediterranean diets based mainly on olive tree products is known. As discussed below, the major active ingredient of the leaves and oil of Olea europaea is oleuropein and the majority of polyphenols found in olive oil or table olives are derived from its hydrolysis. Oleuropein is a novel, naturally occurring antioxidant compound, which may possibly be used to prevent cancer and cardiotoxicity induced by doxorubicin. Searching for medicinal benefits from edible or inedible plants is not a novel idea since numerous modern medicines have plant origins. Given that the ingestion of some plant foods results in reduced risk for cancer, researchers are delving into the identification of phytochemicals with cancer preventive ability in studies in vitro, in vivo, and those in humans. Phytochemicals can be roughly classified into four groups based on their mechanisms of chemopreventive and therapeutic properties, as shown in Table 1.

In the following paragraphs, we will focus on nine widely used herbs that are commonly used in the context of cancer by patients in the Middle East: Olive, black seeds, saffron, pomegranate, nettle, Garlic, onion, Palestinian arum, and grapes [2, 3, 5, 31–33]. Other commonly used medicinal plants and wild edible plants are described in Table 1 and [30].

4.5. Olea Europea (Olive)
O. europaea (the olive) is a species of the family Oleaceae. The olive tree is an evergreen tree or shrub native to the Mediterranean, Asia, and the Maghreb region. Olive leaf and olive leaf extracts are now marketed as antioxidants, antiaging, immunostimulators, and even antibiotics. Clinical evidence has proven the antidiabetes and antihypertension effects of leaf extracts. In addition, several studies support its antibacterial, antifungal, and anti-inflammatory properties [34–36].

Epidemiological studies provide convincing evidence for a protective effect of the Mediterranean diet against cardiovascular disease and cancer [37, 38]. These findings prompted scientists to search for Mediterranean flora as a rich source of bioactive phytochemicals with a potential to evolve into preventive and possibly therapeutic agents. Much epidemiological evidence suggests that people who consume an olive oil rich diet have a lower incidence of certain cancers, including breast, skin, and colon [34]. The lower incidence of certain cancers is most likely associated with the antioxidant activity of active ingredients of the olive oil. Oxidative stress has been shown to contribute to cancer development, and antioxidants are believed to reduce the risk of mutagenesis and carcinogenesis. Hydroxytyrosol was found to be capable of protecting cells from hydrogen peroxide damage and DNA from peroxynitrite-induced damage, blocking cell cycle progression at the G1 phase, and inducing apoptosis [39]. In vivo and in vitro studies on the activity of oleuropein have found that, in addition to antioxidant properties, it has antiangiogenic action and inhibits cell growth, motility, and invasiveness. Oleuropein was also found to cause cell rounding, which disrupts the cell actin cytoskeleton. Oleuropein also affects and disrupts purified actin filaments, providing direct antitumor effects due to cell disruption. In in vivo animal studies, rapid tumor regression was observed when mice were given one percent oleuropein in drinking water [40]. Saturated animal fats and polyunsaturated plant fats in the diet have been implicated in colon, breast, prostate, and ovarian cancers. The vast usage of olive oil in the Mediterranean diet may explain its apparent cancer-protective effect, rather than the amount of fat consumed. Furthermore, in a recent study evaluating the antioxidant and antiproliferative activity of water and methanol olive leaves extracts in cancer and endothelial cells, olive leaf crude extracts were found to inhibit proliferation of cell from a human breast adenocarcinoma, cells from human urinary bladder carcinoma (T-24), and cells from bovine brain capillary endothelial (BBCE) [39, 41, 42].

4.6. Nigella Sativa (Black Seeds)
N. sativa of the Ranunculaceae family is one of the most commonly used medicinal plants throughout the Middle East. N. sativa seeds have been used for centuries as a spice and food preservative, as well as a protective and curative remedy for numerous diseases. The seeds are known to have many medicinal properties and are widely used in Greco-Arab and Islamic medicine. The plant is found wild in North Africa, the Mediterranean region, Asia Minor, and in Southern Europe. N. sativa is one the most referenced medicinal seeds in history. In many civilizations the herbal spice N. sativa was referred to as Habbat-el-barakah (literally seeds of blessing in Arabic), Kalonji (Hindi), Kezah (Hebrew), Sijah Daneh (Persian) and Black Caraway in English. The famous Greek physician dioscorides [40–42, 44, 45, 57, 59, 71–114] used black seeds to treat headaches and toothaches. N. sativa seeds and oil extracts have been widely used for centuries to treat disorders in the respiratory system, stomach, kidney and liver function, and circulatory, immune system as well as cancer. In Islam, it was regarded as one of the greatest forms of healing medicine available [71]. Prophet Mohammad (PBUH) stated “The black seed can heal every disease, except death” [21]. Avicenna referred to black seed in his “Canon of Medicine” as the seed that stimulates the body’s energy and helps recovery from fatigue and dispiritedness. In the Unani Tibb system which is still practiced in central Asia and India seeds are regarded as a valuable remedy for a number of diseases. The seed’s oil was used to treat skin conditions such as eczema and burns and to treat cold symptoms.
Modern research studies showed that N. sativa seeds ethanol extract possesses antitumor activity in mice implanted with tumor primary cells [72]. N. sativa seed extracts contain amino acids, proteins, carbohydrates, alkaloids, saponins, fixed, and volatile oils.

Thymoquinone has been found to be the main compound responsible for the pharmacological properties of the volatile oil of N. sativa. The biological activities and therapeutic potential of thymoquinone are discussed in details by Salem [73]. In brief, thymoquinone was found to possess potent anticancer and antioxidant abilities in animal models and cell culture systems. It acts as an antioxidant and inhibited iron-dependent microsomal lipid peroxidation, cardiotoxicity induced by doxorubin in rats, and inhibited ifosfamide-induced damage in kidney. It also prevented liver injury induced with carbon tetrachloride, lowered drug-induced toxicity and causes amelioration in the drug’s anticancer activity. There are studies reporting that the anticancer potential of thymoquinone is related to its pro-oxidant activities. In human colon cancer cell cultures and in isolated rat liver mitochondria, thymoquinone induced a significant release of reactive oxygen species and inhibited the activity of aconitase, an enzyme sensitive to superoxide anion generation. One of the most promising effects of thymoquinone is its high cancer specificity and low toxicity to normal cells. This has been observed in prostate cancer, colon cancer, canine osteosarcoma, and skin cancer [74, 75]. Many multi-drug-resistant variants of human pancreatic adenocarcinoma, uterine sarcoma, and leukemia were found to be sensitive to thymoquinone [76]. These findings provide further support to the great potential of developing synthetic derivatives of thymoquinone as anticancer agents. Thymoquinone induces apoptosis through modulation of multiple targets and hence is a promising phytochemical agent that could be used for killing many types of cancer cells, such as prostate cancer cells. Thymoquinone blocked angiogenesis in vivo, prevented tumor angiogenesis in a xenograft human prostate cancer model in mouse, and inhibited human prostate tumor growth with almost no side effects. In vivo, thymoquinone inhibited the growth of prostate and colon tumors implanted in nude mice with no noticeable side effects. In colon xenografts, growth inhibition by thymoquinone was not due to decreased proliferation but rather to the significant induction of apoptosis. However, in androgen-independent prostate tumor xenografts, the suppression of tumor growth was associated with a massive apoptosis [77]. These results indicate that the antitumor activity or cell growth inhibition could in part be due to the effect of thymoquinone on cell cycle [75].
Although N. sativa seeds and oil are recognized safe, only a few studies have addressed its potential toxicity. In one study, serum gamma-glutamyl transferase and alanine aminotransferase concentrations were significantly increased after water extracted black seeds were administered orally to rats for 14 days. However, no evident pathological changes were reported [78]. Black seeds oil toxicity was tested in another study in mice and rats through examination of possible biochemical, hematological, and histopathological changes. LD50 was 28.8 mL/kg body for single (acute) oral determination dose and 2.06 mL/kg for intraperitoneal administration [79].
Chronic toxicity was studied in rats treated with an oral dose of 2 mL/kg daily for 12 weeks. No changes were reported neither in key hepatic enzymes levels (i.e., ALT, AST, and GSH), nor in histopathological modifications (heart, liver, kidneys, and pancreas). Nevertheless, serum cholesterol, triglyceride, and glucose levels as well as the count of leukocytes and platelets decreased significantly and slowing of body weight gain was reported. Some other studies had reported black seeds and thymoquinone toxicity in rats and mice when exposed to high doses [79–81]. Taken together, a degree of caution is necessary with larger amounts of Nigella sativa due to the presence of thymoquinone and other active ingredients.

4.7. Crocus Sativus (Saffron)
Saffron has a long history as part of traditional healing. Modern medicine has also discovered saffron as having anticarcinogenic, antimutagenic, immunomodulating, and antioxodant-like properties [82]. Saffron contains several active compounds including, but not limited to, flavonoids, tannins, carotenoids, anthocyanins, alkaloids, and saponins. A number of in vitro and in vivo studies have reported an antitumor properties of saffron [44, 82–85]. Pretreatment with saffron prevented oxidative stress induced by DMBA (7,12-dimethylbenz[?]anthracene), known to generate DNA-reactive species and skin carcinoma in mice [83]. These effects are contributed to an active compound, crocetin [86, 87], that exhibited antitumor activity in a lung cancer animal model by scavenging free radicals and drug metabolizing enzymes [88]. It also inhibited pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model and downregulated growth and proliferation stimulated apoptosis and resulted in significant growth regression in pancreatic tumors. However, it is not known whether the effect of crocetin on pancreatic cancer regression is its own receptor-dependent or receptor-independent mechanisms [89].
Crocetins antitumor activity was evaluated in several cancer cell lines [86, 87]. For instance, crocetin inhibited MCF-7 and MDA-MB-231 breast cancer cell lines proliferation [82, 84, 90] via downregulation of matrix metalloproteinases [45]. Crocetin and carotenoids, in general, showed cytotoxic effects on a range of tumors and malignant cells [82]. It had interfered with DNA transcription as well as DNA, RNA, and protein synthesis through suppression of the activity of DNA-dependent RNA polymerase II [44]. Crocetins LD50 is relatively high (2 g/kg) [82, 84, 90] raising the possibility that it could be relatively nontoxic with a potential to exert an antitumor effect.

4.8. Punica Granatum (Pomegranate)
Pomegranates have been used for a long time in traditional Greco-Arab and Islamic medicine for the treatment of a variety of ailments, including sort throat, inflammation, and rheumatism. It was also used for treating bladder disturbances, strengthening gums, and soothing mouth ulcers. Pomegranates feature prominently in all religions: Islam, Judaism, Christianity, Buddhism, and Zoroastrianism. According to the Qur’an pomegranates grow in the gardens of paradise. Among the small number of fruits and vegetables mentioned in the Qur’an, (including date, olive, grape, banana, fig, cucumber, garlic, lentil, and onion), pomegranate was mentioned three times, indicating its significance in Muslims life. This fruit was consumed as fresh or in the form of juice. Pomegranate is known as an antioxidant agent and is used to treat several diseases including cancer, inflammation, cardiovascular disease, diabetes, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage [91–93]. Yet, for the most part, research is focused on its antioxidant, anti-inflammatory, and anticarcinogenic properties.

4.9. Pomegranate Juice
Pomegranate Juice is a rich source of antioxidant tannins, flavonoids (quercetin), and some other antitumor compounds. Recent research has shown that pomegranate juice selectively inhibited the growth of breast, colon, and lung cancer cells in culture, decreased proliferation and induced apoptosis of DU-145 prostate cancer cells and suppressed invasive potential of PC-3 cells. These effects may be associated with the plant-based anti-inflammatory effects [94, 95]. Pomegranate juice was also effective in inhibition of inflammatory cell signaling in colon cancer [96]. In preclinical animal studies, oral consumption of pomegranate extract inhibited growth of lung, skin, colon, and prostate tumors [95, 96]. Pomegranate fruit extract was also effective in inhibition of lung tumorigenesis in mice [97]. Thus, pomegranates consumption could potentially help in reducing the growth and spread of prostate and lung cancer cells or even prevent cancer from developing. Pomegranate juice has also shown an initial promise in a phase II clinical trial against prostate cancer [98]. Pomegranate juice given to men with rising prostate specific antigen (PSA) following surgery or radiation offered positive and beneficially significant effects on PSA parameters, suggesting a potential of pomegranate-derived products for prevention of human prostate cancer [91].

4.10. Pomegranate Seeds
Up to 20% of the pomegranate seed weight is oil especially fatty acids (manly is triacylglycerols) [99]. Pomegranate seeds matrix includes also lignines and some of its derivates possess antioxidant activity [100]. The seeds oil had beneficial outcome in inflammation downregulation and thus cancer preventive effects. For instance, it had inhibited PC-3 prostate cancer cell line phospholipase A2 expression [94] and upregulated MAPK-APK2 in DU-145 prostate cancer cells [57]. In mouse model, 1 ?g/mL seed oil suppressed tumor occurrence almost completely in mammary organ culture [101] and colon carcinogenesis induced by azoxymethane [102]. External treatment with 5% seeds oil produced significant decreases in mouse skin tumor incidence and multiplicity [103]. The oil also downregulated proangiogenic vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells and induced apoptosis in human breast cancer cells [104].

4.11. Pomegranate Peel
Traditionally, pomegranate peels are dried, decocted in water, and employed both internally and externally to heal aphthae and diarrhea. Pomegranate peel has been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasion, and angiogenesis [101]. Pomegranate peel extract delays the proliferation of human breast and prostate cancer cell lines [105]. Pomegranate peel and juice contain several active compounds (i.e., catechins, epicatechins, proanthocyanidins, anthocyanidins, quercetin) known to be principal for cell cycle arrest, proliferation prevention, and apoptosis initiation [106].
More specifically, catechins and epicatechins possess antiangiogenic, antioxidant, and anticarcinogenic activities [107]. They also inhibited cyclooxygenase activity, nitric oxide production, and the epidermal growth factor receptor [108].
Quercetin is well known for its anticancer activity. It had inhibited lung cancer cell growth via cell cycle arrest and apoptosis induction [109]. More recently, Park and Min showed that quercetin induces downregulation of phospholipase D1 and thus inhibited proliferation and invasion in glioma (U87) cells [110]. Quercetin anticancer beneficial effects were also evaluated in animal models [111] and in clinical trials [59]. The anticarcinogenic effects of the other isolated fractions and compounds of the pomegranate were described elsewhere [92, 112].

4.12. Urtica Dioica (Nettle)
The origin of its Latin name, Urtica, means “I burn”, indicative of the stings caused by glandular hairs on the leaves that contain formic acid and histamine, two agents known to cause the stinging and skin irritation after contact. U. dioica leaf has a long history as an herbal remedy and nutritious addition to the diet. Nettle leaves are a rich source of essential amino acids, ascorbic acid, several mineral element, and vitamins, such as iron, provitamin A, and vitamin C [113]. Nettle extracts can be used to treat arthritis, hay fever, kidney problems, pain, and anemia. Nettle extracts possess hypoglycaemic properties and improve glucose tolerance [35]. U. dioica is believed to be antioxidant, immunesuppressive, antirheumatoid, antiulcer, anti-inflammatory, and anticarcinogenic [14]. Indeed, its leaf [114] and roots [115] extracts were effective against prostate cancer proliferation.

4.13. Allium Sativum L. and Allium Cepa (Garlic and Onion)
Prophet Mohammad (PBUH) said “although onion and garlic have a bad smell, they are cures for 70 different illnesses that cannot be cured by any other means”. Onion (A. cepa) and garlic (A. sativa) are closely related vegetables that belong to the Allium class of bulb-shaped plants, which also includes chives, leeks, and scallions. Garlic is used for flavoring in cooking and is unique due to its high sulfur content, along with arginine, oligosaccharides, flavonoids, and selenium, all of which might promote health [116].
The association between the consumption of Allium vegetables and the risk for cancer was assessed in several epidemiologic studies, showing the protective effect of garlic and onion on cancer. In China, high consumption of Allium vegetables was associated with lower incidence of gastric cancer [117, 118]. Additional studies in the Netherlands suggested an inverse correlation between the risk of colorectal, breast, and lung cancers and the consumption of onion and garlic [119].
Steinmetz et al. [120] studied the association between garlic consumption and the risk of colon cancer and found that women who consumed high amounts of garlic had a 50 percent lower incidence of distal colon cancer compared with women who consumed less garlic [120]. The risk of breast cancer was also found to be reduced in women consuming greater amounts of fiber garlic and onions [31], as well as that of esophageal and stomach cancers [121]. Similar findings were noted with reference to the risk of prostate cancer [122, 123], pancreatic cancer [33], and other known cancer types [124]. The amount of garlic consumed in the above studies varied from 2 to 20 g daily (The World Health Organization (WHO) guidelines for general health promotion for adults recommend a daily dose of 2 to 5 g of fresh garlic). It was noted that although garlic had been used safely in cooking, excessive consumption can cause some side effects, in addition to those of strong breath and body odors [125]. The protective effect of Allium vegetables against tumor progression and against angiogenesis were attributed to its organosulfur compounds especially allicin (an active compound in garlic) and diallyl disulfide [126]. Such compounds are able to block the formation of cancer-causing substances [127], halt the activation of cancer-causing substances [128, 129], enhance DNA repair [130], reduce cell proliferation, or induce apoptosis-programmed cell death (Table 1 and [126, 131]).
The protective effects of onion and garlic organosulfur compounds against carcinogenesis were also studied in animal models and in vitro. When administrating the above compounds to mice 2–4 days prior to a carcinogen challenge, these compounds inhibited the development of pulmonary adenoma [132]. Intravenous administration of the garlic active compound (diallyl trisulfide) significantly retarded the growth of orthotopically transplanted hepatoma in BALB/c nude mice [133]. These compounds had also halted the proliferation of cancer cell lines, including human lung, skin and colon tumor cell lines, human neuroblastoma cells, human and murine melanoma cells, and human prostatic carcinoma cells [134–137].

4.14. Arum Palaestinum (Palestinian Arum)
Arum is edible plant and is widely used in the Middle-East cooking, especially in the Palestinian kitchen. According to a survey conducted in 2008, Palestinian Arum was found to be one of the most potent anticancerous (especially colon cancer) plant in Palestine [3]. Moreover, A. palaestinum is also effective against internal bacterial infections, poisoning, and disturbances of the circulatory system. Care should be taken especially when using A. palaestinum to treat tumor since it may cause negative side effects. For instance, flavonoid isoorientin (6-C glucoside of luteolin), isolated from A. palaestinum possesses myolytic activity on rat and guinea pig smooth muscle [138]. However, the action mechanism of Palestinian Arum awaits further studies.

4.15. Vitis Vinifera (Grapes)
Grapes exert several health benefits, including, but not limited to, anti-inflammatory and anticancer effects and prevent lipid oxidation and platelet aggregation. The main active compound in grapes is the polyphenol compound resveratrol. Resveratrol is believed to decrease circulating LDL (low-density lipoprotein) and cholesterol and thus reduce the risk of cardiovascular diseases [139]. Grapes, as many other fruits and vegetables, are rich in antioxidant compounds called flavonoids. They are among the plant chemicals that have shown a potential benefit against heart disease. Flavanoids as well as the whole black grape (including seeds) were shown to inhibit key enzymes in tumor cell, thereby inducing apoptosis and or blocking their growth [140, 141]. In rats, grape seeds extracts (proanthocyanidins) reduced the progress of ulcerative colitis thereby decreasing the risk of colorectal cancer [142].

5. Discussion
During the Arab-Islamic Golden Age, collaborative works of physicians and scientists from different nations and ethnic groups raised the dignity and caliber of the medical profession. Disease was seen by Arabs and Muslim physicians as a problem that can be challenged. The Prophet (PBUH) was credited with many statements on health care problems and their treatments. For instance, “The one who sent down the disease sent down the remedy.” and “For every disease, God has given a cure.” He was also credited with articulating several specific medical treatments, including the use of honey, olive oil, figs, and cupping. Regarding cancer, Avicenna, Rhazes, and Al-Zahrawi have influenced the field of oncology, by establishing clinical approach and therapeutic means (i.e., surgery) which inspired medical research for five centuries. Contemporary research supports the potential of herbs used in Islamic medicine for patients with cancer. More research is warranted regarding the potential benefit of traditional Islamic herbs in alleviation of chemotherapy side effects and improved patients’ quality of life. This line of research may bridge past wisdom with present needs and future perspectives, thus fostering comprehensive cancer treatment attuned to the social and religious concerns of patients all over the Middle-East.

Despite the rapidly increasing understanding of the molecular and cellular processes, the morbidity of cancer is still on the rise. Cancer epidemiology has revealed that certain cancers are more common among people of different cultures and ethnicities, such as cancer of the lung, colon, prostate, and breast, which are very common in western societies, while they are not as prevalent in eastern societies. The prevalence of cancer in the developing countries is increasing, and the global burden of cancer is estimated to approximately double between 2008 and 2030 from 12.4 million new cases per year to around 26.4 million. A majority of this increase will occur in developing countries where the health services are least able to cope with the challenge. This inequality is highlighted by the markedly lower cancer survival rates in these regions (including Arab-Islamic countries) [143], and the best way to treat cancer is by preventing it and diagnosing it at earlier stages.
Past medical literature is a valuable source of information which entails potential research topics for contemporary scientific work. Several studies have already referred to the biological activities of natural products such as stimulation of the immune system, antibacterial, antiviral, antihepatotoxic, antiulcer, anti-inflammatory, antioxidant, antimutagenic, and anticancer effects [2, 125, 144–146]. A variety of grains, cereals, nuts, soy products, olives, beverages such as tea and coffee, and spices including turmeric, garlic, ginger, black pepper, cumin and caraway confer a protective effect against cancer [31, 33, 125, 145, 147]. Several studies have also documented the relationship between decreased cancer risk and high consumption of vegetables, including cabbage, cauliflower, broccoli, brussels sprout, tomatoes, and fruits such as, apples and grapes [2, 33, 146, 148]. In addition, a number of medicinal plants and herbs have also been reported to reduce the risk of cancer in multiple sites (Table 1 and [149, 150]). With regard to anticancer drugs, various currently used drugs are the derivatives of plant sources including, but not limited to, paclitaxel (taxol), vinblastine, capsaicin, vincristine, the camptothecin derivatives, topotecan, irinotecan, and etoposide (Table 1 and [146, 151–153]). Many commonly used anticancer herbs possess chemopreventive effects within their diverse pharmacological properties. Since cancer evolves over a long period of time, agents that inhibit or retard one or more of its stages could affect the overall course of the disease. Certain micronutrients (like oleuropein and diallyl sulfide compounds found in olives and garlic, resp.) possess potent cancer-preventive capacities.
The authors would like to acknowledge the USDA-Agricultural Research Service (ARS) and Al-Qasemi Research Foundation for providing their financial support.

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