Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro.

Hypoxia is a hallmark of solid tumors, including breast cancer, and the extent of tumor hypoxia is associated with treatment resistance and poor prognosis. Considering the limited treatment of hypoxic tumor cells and hence a poor prognosis of breast cancer, the investigation of natural products as potential chemopreventive anti-angiogenic agents is of paramount interest. Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), the primary anthraquinone in the roots of Cassia alata L., is a naturally occurring quinone which exhibits a variety of biologic activities including anti-cancer activity. However, the effect of rhein on endothelial or cancer cells under hypoxic conditions has never been delineated. Therefore, the aim of this study was to investigate whether rhein inhibits angiogenesis and the viability of hormone-dependent (MCF-7) or -independent (MDA-MB-435s) breast cancer cells in vitro under normoxic or hypoxic conditions. Rhein inhibited vascular endothelial growth factor (VEGF(165))-stimulated human umbilical vein endothelial cell (HUVEC) tube formation, proliferation and migration under normoxic and hypoxic conditions. In addition, rhein inhibited in vitro angiogenesis by suppressing the activation of phosphatidylinositol 3-kinase (PI3K), phosphorylated-AKT (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) but showed no inhibitory effects on total AKT or ERK. Rhein dose-dependently inhibited the viability of MCF-7 and MDA-MB-435s breast cancer cells under normoxic or hypoxic conditions, and inhibited cell cycle in both cell lines. Furthermore, Western blotting demonstrated that rhein inhibited heat shock protein 90alpha (Hsp90α) activity to induce degradation of Hsp90 client proteins including nuclear factor-kappa B (NF-κB), COX-2, and HER-2. Rhein also inhibited the expression of hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF(165)), epidermal growth factor (EGF), and the phosphorylation of inhibitor of NF-κB (I-κB) under normoxic or hypoxic conditions. Taken together, these data indicate that rhein is a promising anti-angiogenic compound for breast cancer cell viability and growth. Therefore, further studies including in vivo and pre-clinical need to be performed.
Source:
Fernand VE, Losso JN, Truax RE, Villar EE, Bwambok DK, Fakayode SO, Lowry M, Warner IM. Chem Biol Interact. 2011 Jul 15;192(3):220-32. Epub 2011 Mar 30.

Cordyceps militaris Grown on Germinated Soybean Induces G2/M Cell Cycle Arrest through Downregulation of Cyclin B1 and Cdc25c in Human Colon Cancer HT-29 Cells

Cordyceps militaris (CM) is an insect-borne fungus that has been used in traditional Chinese medicine because of its wide range of pharmacological activities. In this paper, we studied CM grown on germinated soybean (GSC) and investigated the possible mechanisms underlying antiproliferative effect of GSC on HT-29 human colon cancer cells. In comparison with CM extracts and germinated soybean (GS) BuOH extracts, BuOH extracts of GSC showed remarkable inhibitory and antiproliferative effects on HT-29 colon cancer cells. After GSC treatment, HT-29 cells became smaller and irregular in shape. High G2/M phase cell populations were observed in the GSC-treated group. The levels of cyclin B1 and Cdc25 in the GSC-treated group were lower than those in the control group. These findings suggest that GSC BuOH extracts might act as an effective anti-proliferative agent by inducing G2/M cell cycle arrest in colon cancer cells.
Due to the increasing incidences and relatively low remission rates of colon cancers, there is a need to establish more effective treatment regimens by adopting novel and innovative approaches [16]. The use of active medicinal compounds or extracts from traditional medicines or natural sources is considered as one such alternative treatment approach. Many naturally derived compounds/extracts are considered safe as they are obtained from commonly consumed foodstuffs. CM is a well-known medicinal mushroom that has been used in oriental medicine for treating various diseases, including cancers. Previous studies have demonstrated that CM has a wide range of pharmacological activities, including immunomodulatory and anti-inflammatory activities [7–11].Cancer cells generally exhibit few characteristics such as high proliferation, migration, and matrix-invasion potentials [17, 18]. Inhibition of tumor growth is one of the therapeutic targets in the development of anticancer agents. The regulation of tumor cell growth and the induction of cell death are the 2 major ways to inhibit tumor growth [19]. The present study evaluated whether GSC BuOH extracts had anti-proliferative activities against HT-29 cells. Although GSC BuOH, GS, and CM BuOH extracts exhibited anti-proliferative activity against HT-29 cells, GSC BuOH extracts showed anti-proliferative activity with the lowest IC50 (100 μg/mL) value. Severely distorted HT-29 cells and loss of colony formation ability were observed after GSC BuOH treatment. We analyzed the changes in HT-29 cell cycle progression after GSC BuOH treatment by flow cytometry. Cellular proliferation is controlled by various genetically defined checkpoints, which ensure the progression of cells through the various stages of the cell cycle [20]. In cancer cells, cell cycle checkpoint control systems are known to be disrupted through the accumulation of mutations [21]. In the G2/M phase, damaged cells have the opportunity to repair DNA or permanently arrest cell growth if the degree of damage is severe [22]. Several anticancer agents arrest the cell cycle in G2/M phase, and then induce apoptosis and necrosis, resulting in cell death [23, 24]. In general, the G2/M transition is regulated by a complex of cell-division cyclins, namely, Cdc2 and a B-type cyclin [22]. The protein tyrosine phosphatase, Cdc25c, plays the role of a mitotic activator by dephosphorylating Cdc2/p34, which forms the Cdc2/cyclin B1 complexes that permit cells to enter into mitosis [25]. Many studies showed that Cdc2/p34 kinase activity was enhanced in some human cancer cells because of their genetic and epigenetic alterations [22]. Therefore, we investigated whether the expressions of the molecules involved in G2/M transition in HT-29 cells were altered after GSC BuOH extract treatment. We found that GSC treatment resulted in downregulation of Cdc25c and cyclin B1 expression in HT-29 colon cancer cells. The results of the present study indicated that GSC caused G2/M-phase cell cycle arrest along with a decrease in the levels of cyclin B1 and Cdc25c, which are involved in cell cycle progression from the G2/M phase. In addition, the identification of such compounds will improve our understanding of the anti-proliferative activities of GSC. Further experiments need to be done to clarify the anti-proliferative mechanisms of these identified compounds.
Source:
Mohammad Lalmoddin Mollah, Dong Ki Park, and Hye-Jin Park. Evidence-Based Complementary and Alternative Medicine Volume 2012. doi:10.1155/2012/249217
References:
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8. H. Lee, Y. J. Kim, H. W. Kim, D. H. Lee, M. K. Sung, and T. Park, “Induction of apoptosis by Cordyceps militaris through activation of caspase-3 in leukemia HL-60 cells,” Biological and Pharmaceutical Bulletin, vol. 29, no. 4, pp. 670–674, 2006. View at Publisher · View at Google Scholar
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11. G. Y. Kim, W. S. Ko, J. Y. Lee et al., “Water extract of Cordyceps militaris enhances maturation of murine bone marrow-derived dendritic cells in vitro,” Biological and Pharmaceutical Bulletin, vol. 29, no. 2, pp. 354–360, 2006. View at Publisher · View at Google Scholar
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19. S. T. Huang, R. C. Yang, L. J. Yang, P. N. Lee, and J. H. S. Pang, “Phyllanthus urinaria triggers the apoptosis and Bcl-2 down-regulation in Lewis lung carcinoma cells,” Life Sciences, vol. 72, no. 15, pp. 1705–1716, 2003. View at Publisher · View at Google Scholar
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Ellagic Acid – Chemopreventive Role in Oral Cancer

Ellagic acid is an antioxidant and an anti-proliferative compound present in fruits, nuts and vegetables. In spite of evidences for anticancer activity in various cancer cell-lines, human cancer cells, the mechanistic role of ellagic acid is not conclusive enough to be recommended for a clinical use. The present review provides information about the chemopreventive role of ellagic acid in oral cancer and proposes molecular basis for ellagic acid’s inhibitory activity against oral cancer. We show that ellagic acid modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin dependent kinase 2, cyclin A2, cyclin B1, cyclin D1, c-myc, PKCα), cell survival/apoptosis pathway (Bcl-XL, Bax, Caspase 9/3, Akt), tumor suppressor pathway (p53, p21), inflaming Metastasis pathways (IL-1 beta, TNF-α, matrix metalloproteinases 9/3, COX-2), angiogenesis pathways (VEGF), cell immortalization (TERT), NF-κβ.
Introduction
Oral cancer is the 10th most common form of cancer worldwide. Developing countries share major global burden of deaths due to oral cancer; countries like India contributes ~ 26% of global oral cancer incidence. Oral cancer is 2nd most common form of cancer among Indian males [1]. Oral cancer is a multi-factorial disease which has implicating attributes like genetics, environmental, life-style and behavioral [2]. Around half of the patients detected for oral cancer will die within 5 years of initial diagnosis. Five year survival rate has not improved in spite of better understanding of cancer at a molecular level and with the advent of rationally targeted drugs [3].
Conclusion
Oral cancer develops by complex interplay between intrinsic and extrinsic factors playing important role in tumor development from primary lesion. The process of expression of tumorigenesis is based on a tightly controlled sequence of events which are dependent on the proper levels of transcription and translation of certain genes. There is a small subset that seems to be particularly important in the prevention, development, and progression of cancer. These genes have been found to be either malfunctioning or non-functioning in oral cancer. It is, therefore, logical to believe that success of any therapy will depend on its effectiveness to modulate these genes controlling different pathways to restore homeostasis. Molecular targets of ellagic acid are the key regulators, spread across all cancer hallmarks, which should make it an effective agent for prevention of oral cancer. Ellagic acid is known to modulate key regulators like NF-κβ, p53 and CK2. The versatility of EA to inhibit oral carcinogenesis through multiple pathways makes ellagic acid a potent chemopreventive agent [4,5].
Source:
Bisen PS, Bundela SS, Sharma A (2012) Ellagic Acid – Chemopreventive Role in Oral Cancer. J Cancer Sci Ther 4: 023-030. doi:10.4172/1948-5956.1000106
References:
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C et al. (2008) Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10.
2. Wake M (1993) The urban/rural divide in head and neck cancer–the effect of atmospheric pollution. Clin Otolaryngol Allied Sci 18: 298-302.
3. Massano J, Regateiro FS, Januario G, Ferreira A (2006) Oral squamous cell carcinoma: Review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102: 67-76.
4. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70.
5. Mantovani A (2009) Cancer: Inflaming metastasis. Nature 457: 36-37.

Cancer Chemoprevention: Prevention is Better than Cure

Rajendra Sharma

Cancer is one of the major causes of morbidity and mortality throughout the world. Carcinogenesis is a multistep molecular process induced by genetic and epigenetic changes that disrupt pathways controlling cell proliferation, apoptosis, differentiation, and senescence [1,2]. Therefore, several diverse approaches are required for the treatment and management of cancer which include radiation, chemotherapy, and surgical removal of malignant tissues.

Consistent with the old English proverb “Prevention is better than cure”, one of the multifactorial approaches to our fight against this dreaded disease is based on prevention of the disease through use of non-toxic dietary supplements, micronutrients and natural compounds. This approach is generally referred to as “chemoprevention” that is defined as the use of natural or synthetic agents that reverse, inhibit, or prevent the development of cancer. Thus the major goal of chemoprevention is to delay the onset of cancer as well as decrease its incidence. An effective chemoprevention requires the use of non-toxic agents that inhibit specific molecular steps in the carcinogenic pathway. It has been advocated that vegetarian diet may be an important source of cancer-inhibiting bioactive phytochemicals [3]. Although these compounds are generally viewed as non-essential for normal body functioning, an increasing number of them have been shown to possess biological activity relevant to disease-fighting and prevention of cancer. Interestingly, a number of population based studies indicate that people in South East Asian countries have much lower risk of developing colon, prostate, breast, lung and other cancers as compared to their Western counterparts. It has been suggested that constituents of their diet such as garlic, ginger, soy, turmeric, onion, tomatoes, cruciferous vegetables and green tea play a significant role in cancer prevention. Recognition of such an importance of diet in cancer prevention has finally lead to an accelerated pace of research in the area of chemoprevention. A number of bioactive compounds have been isolated from garlic, turmeric and cruciferous vegetables which showed significant potential to inhibit carcinogenesis. For example, diallyl disulfides present in garlic [4], isothiocyanates (such as sulforaphane) [5] from cruciferous vegetables, and curcumin [6] isolated from the turmeric have been shown to inhibit growth of various cancer cells types including prostate, breast, lung, colon and leukemia and skin [7]. During late 70s Wattenberg’s research group demonstrated that dietary chemicals including phenolic antioxidants can significantly inhibit chemical induced carcinogenesis in laboratory animals [8]. Studies conducted during last four decades have shown that both natural and synthetic chemopreventive agents essentially inhibit carcinogenesis by two major mechanisms 1) inhibition of carcinogen activation and 2) induction of xenobiotic metabolizing enzymes that protect from the toxic effects of environmental chemicals [9]. Besides these, other molecular targets shown to be inhibited by chemopreventive agents in cancer cells are: a) the proteins involved cell cycle progression and proliferation b) anti-apoptotic proteins c) drug transport, MDR, MRP d) growth factor pathway e) NF-kB activation pathway f) Angiogenesis g) inflammatory proteins such as COX-2 [3-9].

In this Special issue of the Journal of Cancer Science and Therapy on the Chemoprevention of Cancer we have included authoritative Reviews on the chemoprevention of prostate and colorectal cancer as well as original articles describing the efficacies of natural and synthetic chemopreventive agents in inhibition of prostate, lung and acute promyelocytic leukemia. These articles will not only benefit the researchers and clinicians working in this field but also to other scientists interested in exploring the significance of dietary supplements in the prevention of cancer. It is high time to appreciate the fact that economic burden associated with the treatment and management of cancer is huge and prevention of this disease by diet and dietary supplements is important to offset this burden. Basic and clinical research studies have already demonstrated the efficacy of chemopreventive agents in protection against cancer and other chronic diseases. Therefore, it is high time to channelize resources in this direction.
Source:
Sharma R (2012) Cancer Chemoprevention: Prevention is Better than Cure. J Cancer Sci Ther S3:e001. doi:10.4172/1948-5956.S3-e001
References
1. López-Lázaro M (2010) A new view of carcinogenesis and an alternative approach to cancer therapy. Mol Med 16: 144-153.
2. Jaffe LF (2003) Epigenetic theories of cancer initiation. Adv Cancer Res 90: 209-230.
3. Huber MH, Lee JS, Hong WK (1993) Chemoprevention of lung cancer. Semin Oncol 20: 128-141.
4. Conaway CC, Yang YM, Chung FL (2002) Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans. Curr Drug Metab 3: 233-255.
5. Singh AV, Xiao D, Lew KL, Dhir R, Singh SV (2004) Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo. Carcinogenesis 25: 83-90.
6. Fahey JW, Zhang Y, Talalay P (1997) Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci U S A 94: 10367-10372.
7. Fleischauer AT, Arab L (2001) Garlic and cancer: a critical review of the epidemiologic literature. J Nutr 131: 1032S-1040S.
8. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23: 363-398.
9. Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3: 768-780.

How Cancer Spreads By Aggregating Platelets

Science Daily (Aug. 30, 2007)

Scientists have provided new details about how cancer cells spread by surrounding themselves with platelets — the blood cells needed for blood clotting. Katsue Suzuki-Inoue, Associate Professor of Medicine at the University of Yamanashi, Japan, and colleagues have identified for the first time a protein on the surface of platelets that plays a key role in cancer-induced platelet aggregation. These results could help design new drugs that prevent cancer cells from metastasizing, or spreading throughout the body.
“In order to spread, cancer cells release chemicals that make neighboring platelets aggregate and surround the cancer cells, helping them evade the immune system and allowing them to bind to the blood vessels’ inner linings,” Suzuki-Inoue says. “We have discovered how one of these chemicals, called podoplanin, binds to the platelet cells and stimulate their aggregation. Although podoplanin has been known since 1990, how it induces platelet cell aggregation has been a mystery — until now.”

Suzuki-Inoue and colleagues had previously discovered that the snake venom rhodocytin stimulates platelet aggregation by binding to a protein called C-type lectin-like receptor 2 (CLEC-2) located on the surface of the platelets in a way similar to a key (rhodocytin) binding to a lock (CLEC-2).
By studying the details of what happens inside these platelets before and during aggregation, the scientists noticed many similarities with the way platelets aggregate when they are induced by podoplanin from cancer cells. Whether stimulated by rhodocytin or podoplanin, the platelets are slow to aggregate at first and, after they start aggregating, the proteins that are activated inside the platelets are similar in both cases.
Suzuki-Inoue and her team reasoned that maybe CLEC-2 binds not only to rhodocytin but also to podoplanin. The scientists tested this hypothesis by first growing CLEC-2 in culture and then by adding them to cultured cells expressing podoplanin. The hypothesis was confirmed: CLEC-2 and podoplanin bound to each other in the same lock-and-key mechanism displayed by CLEC-2 and rhodocytin.
“We were pleasantly surprised,” Suzuki-Inuoue says. “After all these years, we finally found the long-missing protein to which podoplanin binds to promote platelet aggregation.”

The scientists confirmed their findings by mixing podoplanin-expressing cells with platelet cells genetically altered so that the CLEC-2 on their surface could not bind to podoplanin. Platelet aggregation was completely inhibited, confirming that CLEC-2 was the protein necessary for podoplanin-induced platelet aggregation.
This result also suggested that it may be possible to prevent cancer cells from stimulating platelet aggregation — and thus allow the cancer cells to metastasize — by blocking the interaction between CLEC-2 and podoplanin.
“Our study clearly shows that podoplanin on the surface of tumor cells induces platelet aggregation by interacting with CLEC-2 on the surface of platelet cells,” Suzuki-Inuoue says. “Preventing CLEC-2 and podoplanin from binding to each other may be a good therapeutic way of preventing tumor metastasis.”
The role of podoplanin-CLEC-2 interaction may not be limited to tumor metastasis, the scientists note. When podoplanin and CLEC-2 bind to each other, not only do platelets aggregate, but they also release chemicals that may form new blood vessels which, in turn, provide the tumor with the nutrients and oxygen it needs to grow. As a result, locking the podoplanin-CLEC-2 interaction may not only prevent cancer metastasis but also limit the growth of cancer cells, Suzuki-Inuoue says.
The researchers also found that podoplanin present within lymphatic vessels — which carry plasma and white blood cells — also induces platelet aggregation, showing that a better understanding of how podoplanin and CLEC-2 bind together may provide information on how lymphatic vessels form and work.
Suzuki-Inuoue and colleagues are now trying to develop antibodies that look like CLEC-2 and that can bind to podoplanin, preventing it from attaching to platelet cells. The scientists are also investigating the role of the podoplanin-CLEC-2 interaction in the formation of blood clots and the development of lymphatic vessels.
The new study, to be published in the September 7 issue of the Journal of Biological Chemistry, was selected as a “Paper of the Week” by the journal’s editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.
Source:
Involvement of the snake toxin receptor CLEC-2 in podoplanin-mediated platelet activation by cancer cells by Katsue Suzuki-Inoue, Yukinari Kato, Osamu Inoue, Mika Kato Kaneko, Kazuhiko Mishima, Yutaka Yatomi, Yasuo Yamazaki, Hisashi Narimatsu, and Yukio Ozaki. The Journal of Biological Chemistry. 2007 282, 25993-26001. doi: 10.1074/jbc.M702327200

Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells.

Olive oil intake has been shown to induce significant levels of apoptosis in various cancer cells. These anti-cancer properties are thought to be mediated by phenolic compounds present in olive. These beneficial health effects of olive have been attributed, at least in part, to the presence of oleuropein and hydroxytyrosol. In this study, oleuropein and hydroxytyrosol, major phenolic compound of olive oil, was studied for its effects on growth in MCF-7 human breast cancer cells using assays for proliferation (MTT assay), cell viability (Guava ViaCount assay), cell apoptosis, cellcycle (flow cytometry). Oleuropein or hydroxytyrosol decreased cell viability, inhibited cell proliferation, and induced cell apoptosis in MCF-7 cells. Result of MTT assay showed that 200 mug/mL of oleuropein or 50 mug/mL of hydroxytyrosol remarkably reduced cell viability of MCF-7 cells. Oleuropein or hydroxytyrosol decrease of the number of MCF-7 cells by inhibiting the rate of cell proliferation and inducing cell apoptosis. Also hydroxytyrosol and oleuropein exhibited statistically significant block of G(1) to S phase transition manifested by the increase of cell number in G(0)/G(1) phase.
Han J, Talorete TP, Yamada P, Isoda H. Cytotechnology. 2009 Jan;59(1):45-53. Epub 2009 Apr 8.

A pilot study on the DNA-protective, cytotoxic, and apoptosis-inducing properties of olive-leaf extracts

Leaves of olive trees are an abundant raw material in the Mediterranean basin. They contain large amounts of potentially useful phytochemicals and could play beneficial roles in health care. In the present study, the principal bioactive phenols in olive-leaf extracts (OLEs) have been identified and quantified, and their genotoxic/antigenotoxic, cytotoxic and apoptotic effects have been assessed. The Somatic Mutation and Recombination Test (SMART) in wing imaginal discs of Drosophila melanogaster has been performed to test the possible genotoxicity of overall OLE and the individual components oleuropein and luteolin at different concentrations. The same assay was able to detect antigenotoxic activity against hydrogen peroxide as oxidative genotoxicant. None of the extracts/phenols tested showed significant mutagenic activity. This fact, together with the antigenotoxic activity against H(2)O(2) detected for all these extracts/phenols, confirmed the safety of OLE, oleuropein and luteolin in terms of DNA protection. HL60 human promyelocytic leukemia cells were used to assess the cytotoxic effects of the extracts/phenols. OLE, oleuropein and luteolin showed a dose-dependent cytotoxic effect with different IC50 (10μl/ml, 170μM, and 40μM, respectively). DNA fragmentation patterns and cell staining with acridine orange and ethidium bromide indicated that the mechanism for the cytotoxic effect of OLE, oleuropein and luteolin was the apoptotic pathway, with DNA laddering and cytoplasmic and nuclear changes. These results could help explain the mechanism of action that underlies the beneficial effect of OLE, proposed as a nutraceutical in the prevention of human cancer.
Anter J, Fernández-Bedmar Z, Villatoro-Pulido M, Demyda-Peyras S, et al. Mutat Res. 2011 Aug 16;723(2):165-70. Epub 2011 May 20.

Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other olive phenolic compounds in human blood mononuclear cells and HL60 cells.

Our aim in this study was to provide further support to the hypothesis that phenolic compounds may play an important role in the anticarcinogenic properties of olive oil. We measured the effect of olive oil phenols on hydrogen peroxide (H(2)O(2))-induced DNA damage in human peripheral blood mononuclear cells (PBMC) and promyelocytic leukemia cells (HL60) using single-cell gel electrophoresis (comet assay). Hydroxytyrosol [3,4-dyhydroxyphenyl-ethanol (3,4-DHPEA)] and a complex mixture of phenols extracted from both virgin olive oil (OO-PE) and olive mill wastewater (WW-PE) reduced the DNA damage at concentrations as low as 1 micromol/L when coincubated in the medium with H(2)O(2) (40 micromol/L). At 10 micromol/L 3,4-DHPEA, the protection was 93% in HL60 and 89% in PBMC. A similar protective activity was also shown by the dialdehydic form of elenoic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) on both kinds of cells. Other purified compounds such as isomer of oleuropein aglycon (3,4-DHPEA-EA), oleuropein, tyrosol, [p-hydroxyphenyl-ethanol (p-HPEA)] the dialdehydic form of elenoic acid linked to tyrosol, caffeic acid, and verbascoside also protected the cells against H(2)O(2)-induced DNA damage although with a lower efficacy (range of protection, 25-75%). On the other hand, when tested in a model system in which the oxidative stress was induced by phorbole 12-myristate 13-acetate-activated monocytes, p-HPEA was more effective than 3,4-DHPEA in preventing the oxidative DNA damage. Overall, these results suggest that OO-PE and WW-PE may efficiently prevent the initiation step of carcinogenesis in vivo, because the concentrations effective against the oxidative DNA damage could be easily reached with normal intake of olive oil.
Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, et al. J Nutr. 2008 Aug;138(8):1411-6.