Chronic inflammation and cancer

25th Monday, 2014  |   Cancer  |  no comments

1476-9255-11-23-2-l NF-?B and p53 antagonises each others activity. Various mediators involved in the pathways are indicated. In addition, p53 and NF- ?B can inhibit each other by direct physical interaction through their multimerization domain. Eventually, the effect of activation NF- ?B pathway prevents the activation of p53 pathway and vice versa. The detail is described in the text. The black colored upward arrows adjacent to NF- ?B and p53 indicate activation of these transcription factors. MDM2: mouse double mute 2; ?-TrCP1: beta transducing repeat containing protein1; ARF: alternate reading frame of INK4/ARF locus; ATR: ATM-Rad3 related; CHK: check point kinase; I ?B: inhibitior of kB; IKK: inhibitor of kappaB kinase. Cancer is an extremely complex disease caused by cells that have lost their usual control over growth. The apparent cause of cancer formation may differ case by case, however the basic mechanism is thought to be the following. There are two classes of genes that can control cancer development. Oncogenes and tumor suppressor genes belong to one class, while the other class belongs to the caretaker genes. Healthy cells follow standard rules of growth and proliferation, and have a definitive life span. In contrast, cells with an oncogenic activation undergo much faster cell division with an indefinite life span. Tumor suppressor genes are evolved to inhibit deregulated cell growth. Usually cancer formation ensues when activation and inactivation of an oncogene and a tumor suppressor gene, respectively, occur in a cell at the same time. The caretaker genes control the rate of mutation in the genome. A defective caretaker gene would allow accumulation of mutation in the genome and thus leading to a higher rate of tumor formation. Therefore, cancer formation occurs due to functional defects in multiple genes. Heredity plays important role in cancer formation. However, it appears to be a small causal factor compared to incidence attributed to the modern lifestyle and environment. Smoking, high calorie diet, obesity, alcohol consumption, chronic infection, exposure to radiation and environmental pollutants are considered to be the major risk factors for cancer formation [1]. In fact about 95% cancer can link modern life style and environment with inflammation as the basic underlying cause [2]. An acute inflammatory response is transient, self regulatory and protects our tissues from infection in a healthy cell. The level of pro-inflammatory cytokines that rises to the peak at the height of the response eventually leads to the production of anti-inflammatory cytokines [3]. Thus an acute inflammatory response is faded off to complete the process of healing. In contrast, chronic or persistent tissue inflammation or irritation is correlated with adverse effects and has long been linked with increasing rate of tumor formation by epidemiological studies [4-6]. Cancer promoted by chronic inflammation (called ‘arbuda’) has been cited in Ayurveda, a form of Indian traditional/alternative medicine ˜5000 years ago. Virchow (in 1858) also had observed frequent cancer origination at the site of chronic irritation [4]. Activation of nuclear factor-kappa B (NF- ?B) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- ?B favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- ?B activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- ?B signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. Pal et al., [5] discuss the role of NF- ?B in chronic inflammation and cancer, highlighting mutual antagonism between NF- ?B and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism. NF- ?B, a central regulator of innate immune response, normally is activated in a time dependent manner as a host protection mechanism. It has been now established by numerous independent studies that a persistent long term activation of this factor is tumorigenic and blockade of the activities of an inflammatory mediator regress tumor progression as well as its aggressiveness. Studies from various independent laboratories have already pinpointed some mediators in the NF- ?B activation pathway that undergo aberrant regulation in various cancers. Studies from many laboratories have firmly established a reverse correlation of activation between the NF- ?B and p53 pathways highlighting a prospective avenue in cancer chemotherapy. Several small molecules of natural or synthetic origin many of which target multiple signaling pathways including NF- ?B and p53 apparently hold a great promise to move the cancer treatment and management in the desired direction. In this direction, various potential pharmacological agents have been isolated that activate p53 in tumor cells with high potency at very low concentration. Most of these small molecules appears to have at least part their mode action through inhibition of NF- ?B. Conversely, it is conceivable that the anticancer activity of many NF- ?B inhibitors is partly due to their ability to induce p53 in cancer cells. Efforts are already underway to find small molecules that will with higher specificity rectify the defect in the pathways to suppress NF- ?B activity. Clearly, more studies are needed to provide us with more insightful understanding of the mechanism of deregulation and the underlying cause. Given the role of NF- ?B in innate immunity and cancer, a desired objective would be to achieve the ability to turn off and on the function of NF- ?B with high precision and as needed. References 1. Stein CJ, Colditz GA: Modifiable risk factors for cancer. Br J Cancer 2004, 90:299-303. 2. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB: Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-2116. 3. Rossi AG, Sawatzky DA: The Resolution of Inflammation. Birkhauser: Basel; 2008. 4. Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001, 357:539-545. 5. Pal S, Bhattacharjee A, Ali A, et al. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism. Journal of Inflammation. 2014, 11:23 doi:10.1186/1476-9255-11-23 http://www.journal-inflammation.com/content/11/1/23

The Possibility of Traditional Chinese Medicine as Maintenance Therapy for Advanced Non-small Cell Lung Cancer

18th Monday, 2014  |   Lung Cancer  |  no comments

Xu Wr, Yang Gw, Xu Ym, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2014 (2014) http://dx.doi.org/10.1155/2014/278917 PastedGraphic-1 Lung cancer has become the leading cause of cancer deaths, with nonsmall cell lung cancer (NSCLC) accounting for around 80% of lung cancer cases. Chemotherapy is the main conventional therapy for advanced NSCLC. However, the disease control achieved with classical chemotherapy in advanced NSCLC is usually restricted to only a few months. Thus, sustaining the therapeutic effect of first-line chemotherapy is an important problem that requires study. Maintenance therapy is given for patients with advanced NSCLC if three is no tumor progression after four to six cycles of first-line platinum-based chemotherapy. However, selection of appropriate maintenance therapy depends on several factors, while traditional Chinese medicine (TCM) as maintenance therapy is recommended for all kinds of patients. It has been demonstrated that TCM can prolong the survival time, improve the quality of life (QOL), and reduce the side effects for advanced NSCLC. Although the trials we searched about TCM serving as maintenance therapy is only 9 studies, the results indicate TCM can prolong the progression free survival (PFS) and improve the QOL. So it is possible for TCM to be as maintenance therapy for advanced NSCLC. Lung cancer has become the leading cause of cancer deaths in both men and women [1, 2]. Nonsmall cell lung cancer (NSCLC) accounts for around 80% of lung cancer cases [3]. At diagnosis, approximately 70% of patients present advanced stage of malignancy, for which curative therapy will not be available. Chemotherapy, radiotherapy, and targeted therapy are the conventional treatment for advanced NSCLC, among which chemotherapy is the main one. Platinum based doublets chemotherapy is the standard of care for advanced NSCLC. However, the disease control achieved with classical doublets chemotherapy in advanced NSCLC is usually restricted to only a few months [4–6]. About 20–80% of NSCLC patients cannot receive second-line chemotherapy for multiple reasons, including poor compliance [7]. Maintenance therapy can suppress disease progression and provide the opportunity to receive additional treatment. Thus, sustaining the therapeutic effect of first-line chemotherapy is an important problem that requires study. In recent years, maintenance therapy has become a new treatment strategy that aims to sustain a reduced tumor size and relieve tumor-related symptoms, in contrast to conventional chemotherapy that aims to maximize tumor cell death [7]. Maintenance therapy is an option in the National Comprehensive Cancer Network (NCCN) Guidelines only for responding and stable disease patients. Many clinical studies of multiple regimens and modalities about maintenance therapy are currently underway, which has been shown to improve the progression free survival (PFS) [8, 9]. However, some concerns remain regarding the overall survival (OS) and quality of life (QOL) [10]. The application of these chemotherapeutic drugs and molecular targeted drugs in maintenance therapy increase the financial burden of cancer treatment, which is another concern of this therapy. Traditional Chinese medicine (TCM) has increasingly become popular in the west including in cancer patients [11]. It is estimated the United States National Cancer Institute (NCI) spends around $120 million each year on complementary and alternative medicine (including TCM) related research projects [12]. It has been demonstrated that TCM can alleviate the clinical symptoms, improve the QOL, and reduce the side effects [13]. It helps NSCLC patients to “survive with tumor.” So TCM is very suitable for maintenance therapy. In fact, TCM is widely used for NSCLC patients as consolidation therapy which actually includes TCM maintenance therapy. The difference is that maintenance therapy is between first-line and second-line therapy. TCM is endowed with new meaning as the introduction of the concept of maintenance therapy. If the disease is not progressed after first-line therapy, the tumor will be suppressed temporarily. The progression of the tumor is inevitable as time goes by. It is possible to stabilize the tumor, prolong the time to progression, and improve the QOL given with TCM maintenance therapy. Moreover, maintenance therapy is only recommended for patients with performance status (PS) 1-2, while TCM maintenance therapy is recommended for all kinds of patients no matter PS 1-2 or PS 3-4. So it is possible for TCM to be as maintenance therapy for advanced NSCLC. We searched the following sources up to March 2014 using PubMed, CNKI (China National Knowledge Infrastructure), Wanfang Database. Keywords searched were “maintenance therapy” “wei chi zhi liao”, “nonsmall cell lung cancer” “fei xiao xi bao fei ai” or “NSCLC.” No language restriction was applied. After screening titles and/or abstracts, 9 articles were included involving TCM as maintenance therapy in the treatment of advanced NSCLC from the electronic and manual searches. These trials were all conducted in China and published in Chinese. The characteristics of the 9 trials were summarized in Table 1. Most of these trials are small sample, randomized controlled studies. The results indicate that TCM as maintenance therapy can improve the QOL. Part of the studies show that TCM can prolong the PFS compared with the control group (follow-up group). Among them, one study shows that TTP in TCM group is equivalent to that of chemotherapy group, but shows better QOL. Furthermore, there is another study with 162 patients involved from 1992–2007 [14]. It is a nonrandomized controlled study aiming to evaluate the efficacy of TCM as consolidation treatment after conventional therapy. 162 IIIA-IV NSCLC patients after conventional therapy were assigned into TCM group (decoction was applied after conventional therapy) and control group (follow-up after conventional therapy). The results showed that the 2-year and 3-year survival rate of TCM group were much higher than those of the control group. The MST of TCM group was 18 months, while that of control group was 12 months. So it supports that TCM as consolidation therapy can prolong the MST and improve the 2-year, 3-year survival rate. Although the IIIA-IV NSCLC patients after conventional therapy were included into this trial, which did not meet the criteria of maintenance therapy (advanced NSCLC after first-line chemotherapy with no tumor progression), it suggested that advanced NSCLC patients can benefit from TCM consolidation therapy to some degree. PastedGraphic-2 Summary Maintenance therapy with chemotherapy or targeted agents can prolong the PFS of advanced NSCLC patients to some degree, but chemotherapy may increase the toxicity and the risk of drug resistance, and targeted therapy is very expensive and only suited for certain patients with specific genetic alternation [43]. So some patients lose the opportunities to accept maintenance therapy. TCM is widely used in China for cancer patients. Although the effects of TCM in eradicating cancer cells are not obvious, it helps cancer patients to fight against cancer and restore the body into a balanced state by regulating the balance of yin and yang. Besides, TCM can be applied for NSCLC patients not limited in population selection. Recent studies demonstrate that TCM as maintenance therapy can improve the QOL of advanced NSCLC patients. There is some encouraging evidence of TCM for prolonging the PFS. However, there are only small sample clinical trials about TCM as maintenance therapy for advanced NSCLC. More large-scale trials of TCM as maintenance therapy for advanced NSCLC are expected. References 1. P. Guo, Z. L. Huang, P. Yu, and K. Li, “Trends in cancer mortality in China: an update,” Annals of Oncology, vol. 23, no. 10, pp. 2755–2762, 2012. View at Publisher · View at Google Scholar · View at Scopus 2. R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2013,” CA Cancer Journal for Clinicians, vol. 63, no. 1, pp. 11–30, 2013. View at Publisher · View at Google Scholar · View at Scopus 3. K. Zarogoulidis, P. Zarogoulidis, K. Darwiche, et al., “Treatment of non-small cell lung cancer (NSCLC),” Journal of Thoracic Disease, vol. 5, supplement 4, pp. S389–S396, 2013. 4. J. H. Schiller, D. Harrington, C. P. Belani et al., “Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer,” The New England Journal of Medicine, vol. 346, no. 2, pp. 92–98, 2002. View at Publisher · View at Google Scholar · View at Scopus 5. G. V. Scagliotti, F. de Marinis, M. Rinaldi et al., “Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 20, no. 21, pp. 4285–4291, 2002. View at Publisher · View at Google Scholar · View at Scopus 6. F. Fossella, J. R. Pereira, J. von Pawel et al., “Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 Study Group,” Journal of Clinical Oncology, vol. 21, no. 16, pp. 3016–3024, 2003. View at Publisher · View at Google Scholar

· View at Scopus 7. J. Lee and C. Chung, “Update on the evidence regarding maintenance therapy,” Tuberculosis and Respiratory Diseases, vol. 76, no. 1, pp. 1–7, 2014. View at Publisher · View at Google Scholar 8. P. Fidias and S. Novello, “Strategies for prolonged therapy in patients with advanced non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 28, no. 34, pp. 5116–5123, 2010. View at Publisher · View at Google Scholar · View at Scopus 9. T. E. Stinchcombe and M. A. Socinski, “Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy,” Journal of Thoracic Oncology, vol. 4, no. 2, pp. 243–250, 2009. View at Publisher · View at Google Scholar · View at Scopus 10. C. P. Belani, T. Brodowicz, T. E. Ciuleanu et al., “Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study,” The Lancet Oncology, vol. 13, no. 3, pp. 292–299, 2012. View at Publisher · View at Google Scholar · View at Scopus 11. H. S. Boon, F. Olatunde, and S. M. Zick, “Trends in complementary/alternative medicine use by breast cancer survivors: Comparing survey data from 1998 and 2005,” BMC Women’s Health, vol. 7, article 4, 2007. View at Publisher · View at Google Scholar · View at Scopus 12. L. Jia, “Cancer complementary and alternative medicine research at the US National Cancer Institute,” Chinese Journal of Integrative Medicine, vol. 18, no. 5, pp. 325–332, 2012. View at Publisher · View at Google Scholar · View at Scopus 13. L. H. Yoder, “Let’s talk “cancer prevention”,” Medsurg Nursing, vol. 14, no. 3, pp. 195–198, 2005. View at Scopus 14. J. H. Li, “A clinical comparative study on traditional Chinese Medicine serving as consolidation treatment in patients with advanced non-small cell lung cancer,” Chinese Journal of Lung Cancer, vol. 10, no. 6, pp. 520–522, 2007. 44. Z. Liu, Z. Yu, X. Ouyang et al., “Effects of Feitai Capsule on quality of life in patients with advanced non-small-cell lung cancer: a randomized controlled trial,” Journal of Chinese Integrative Medicine, vol. 7, no. 7, pp. 611–615, 2009. View at Publisher · View at Google Scholar · View at Scopus 45. X. S. Chai, C. X. He, W. Y. Wu, and L. N. Li, “Xiaoji Yin as maintenance therapy in the treatment of survival time of advanced non small cell lung cancer,” Shi Zhen Guo Yi Guo Yao, vol. 22, no. 10, pp. 2547–2548, 2011. 46. Y. Jiang, L. S. Liu, C. J. Li, J. H. Tian, L. P. Shen, and H. G. Li, “Effect of Chinese medicine comprehensive regimen as the maintenance therapy on time to progression and quality of life of patients with advanced non-small-cell lung cancer,” Chinese Journal of Integrated Traditional and Western Medicine, vol. 31, no. 10, pp. 1311–1316, 2011. View at Scopus 47. C. X. Xi, G. Q. Yang, Z. G. Li, and W. X. Tao, “Clinical observations of maintenance therapy with Hechan Pian for patients in intermediate and advanced non small cell lung cancer,” Zhong Liu Fang Zhi Yan Jiu, vol. 38, no. 10, pp. 1170–1172, 2011. 48. D. X. Zeng, Y. Z. Bi, G. F. Sheng, Y. Z. Dong, and H. L. Song, “Effectiveness and safety of single-agent ginsenoside Rg3 maintenance therapy after response to first-line chemotherapy in patients with advanced non small cell lung cancer,” Oncology Progress, vol. 11, no. 6, pp. 554–558, 2013. 49. C. Q. Yang, “Clinical research on adjuvant chemotherapy and maintenance therapy of Fuzheng Xiaoji Yin treatment of non small cell lung cancer in middle and advanced stage,” Zhong Yi Xue Bao, vol. 28, no. 187, pp. 1782–1784, 2013. 50. J. R. Liang and L. H. Zhang, “Rongyan Capsule as maintenance therapy on the effects of survival time of advanced non small cell lung cancer,” Si Chuan Zhong Yi, vol. 31, no. 1, pp. 100–101, 2013. 51. L. Wang, Z. X. Sun, G. Q. Feng, and S. J. Ma, “Effect of maintenance treatment by traditional Chinese medicine syndrome differentiation on life quality and progress-free survival of patients with advanced non small cell lung cancer after chemotherapy,” Zhong Guo Shi Yan Fang Ji Xue Za Zhi, vol. 19, no. 13, pp. 319–322, 2013. 52. Y. F. Wu, S. Xu, J. Jia, and G. Wang, “Effect of maintenance treatment with Shenyi Capsule on survival period of advanced non small cell lung cancer patients after induction chemotherapy,” Guang Zhou Zhong Yi Yao Da Xue Xue Bao, vol. 31, pp. 40–43, 2014.

High Red Meat Intake During Early Adulthood Is Associated with Elevated Risk for Breast Cancer

4th Monday, 2014  |   Breast Cancer  |  no comments

Substituting other sources of protein for red meat might lower risk.

strip-steak

In the Nurses’ Health Study, red meat intake during early adulthood was associated with excess risk for breast cancer in premenopausal women after 12 years of follow-up. Now, the same investigators report on associations between dietary protein intake during early adulthood and risk for breast cancer after 20 years of follow-up; analysis involved 89,000 premenopausal nurses (mean age, 36) who completed dietary questionnaires at baseline. continue reading

Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer

28th Monday, 2014  |   Breast Cancer  |  no comments

Melatonin acts both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression.

melatonin

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the over-expression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases.

Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ER?+) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or where to buy generic cialis in animals subjected to dLEN if they received nocturnal melatonin replacement.

Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.

Source
Dauchy RT, Xiang Sl, Mao Li, et al. http://cialisonline-genericrxed.com/ Cancer Res; 74(15); 1–12. doi: 10.1158/0008-5472.CAN-13-3156

Astragaloside IV

22nd Tuesday, 2014  |   Featured  |  no comments

Cancer: Lung
Action: Immune enhancing, regulatory T cells (Tregs), cytotoxic T lymphocytes (CTLs)

Tumor cells have developed multiple mechanisms to escape immune recognition mediated by T cells. Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme inducing immune tolerance, is involved in tumor escape from host immune systems in mice. Astragaloside IV (AS-IV), an extract from a commonly used Chinese medicinal plant Astragalus membranaceus, has been shown to be capable of restoring the impaired T-cell functions in cancer patients. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of AS-IV.

Zhang et al., used IDO-overexpressed murine Lewis lung carcinoma cells to establish an orthotopic lung cancer model in C57BL/6 mice. Next, tumor growth was evaluated in several different treatment groups: control (saline), AS-IV, paclitaxel, and 1-methyl tryptophan (an inhibitor of IDO). We then analyzed the percentages of various immune cell subsets among the splenic lymphocytes of lung cancer mice by flow cytometry. The level of IDO was measured by real-time PCR and Western blot.

They showed that the growth of tumor was suppressed by AS-IV treatment in vivo. AS-IV also could down-regulate regulatory T cells (Tregs) and up-regulate cytotoxic T lymphocytes (CTLs) in vivo and in vitro. Consistent with its ability to interfere with T-cell immunity, AS-IV blocked IDO induction both in vitro and in vivo.

The results of these studies indicate that AS-IV has in vivo anticancer activity and can enhance the immune response by inhibiting the Tregs frequency and induce the activity of CTLs, which might be related to the inhibition of IDO expression.

Source
Zhang A, Zheng Y, Que Z, et al. (2014) Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO. J Cancer Res Clin Oncol. 2014 Jul 1.

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