By Stephen Daniells, 21-Apr-2009

Soy isoflavones do not increase or decrease the density of breasts, say results of a new clinical trial from the US that support the safety of the supplements.

Postmenopausal women given two different doses of soy isoflavones did not experience any changes in the density of breast tissue, according to results of the Osteoporosis Prevention Using Soy (OPUS) study published in the Journal of Nutrition.

 “These findings offer reassurance that isoflavones do not act like hormone replacement medication on breast density,” wrote the authors, led by Dr Gertraud Maskarinec from the Cancer Research Center of Hawaii.

 Soy isoflavones are naturally occurring oestrogen-like compounds, and supplements are currently marketed as a way of reducing symptoms of the menopause and offer an alternative to hormone replacement therapy.

 Conflicting reports however have clouded the picture about the beneficial effects of soy isoflavones, with some studies indicating that breast cancer cells in mice were stimulated by the isoflavones. Population studies have shown that women with a high-soy diet generally have lower rates of breast cancer.

 “Although we did not observe a beneficial effect of soy-derived isoflavones on mammographic densities during a 2-y randomized trial with .300 women, there was also no sign of any adverse effects,” wrote Maskarinec and her co-workers.

 ”These findings do not exclude the possibility that breast cancer risk may be reduced as a result of isoflavone exposure earlier in life or through alternate mechanisms of action than through mammographic densities.”

 Indeed, findings of a study published last month (Cancer Epidemiology, Biomarkers and Prevention, doi: 10.1158/1055-9965.EPI-08-0405) suggested that high intakes of soy during childhood may reduce a woman’s risk of breast cancer later in life by 58 per cent. Furthermore, the study, limited to Asian Americans, found that high soy intakes during adolescence and as adults were associated with a 20 to 25 per cent reduction.

 New data

 Dr Maskarinec and her co-workers recruited 358 postmenopausal women with an average age of 55 and randomly assigned them to receive a placebo or one of two soy isoflavone groups (80 or 120 mg per day) for two years.

 The authors note that these doses are equivalent to the amounts of isoflavones provided in two to four cups soy milk every day.

Results of mammograms revealed a yearly decrease of 1.6 per cent across all the groups, with no difference between the groups when the results were controlled for age and obesity.

 “The fact that hormone replacement therapy interventions, primarily those with progestins, and not those with estrogens alone, modify breast density while soy isoflavones do not, offers some reassurance to those who have been concerned about adverse effects of soy supplementation on breast cell proliferation,” wrote the researchers.

 “Furthermore, when adult soy exposure was analyzed in relation to breast density, women reporting regular soy intake had a faster decline in mammographic densities than those who did not consume soy foods,” they added.

 While some questions remain over isoflavones and breast cancer risk reduction, the compounds remain popular as an alternative to hormone replacement therapy for those wishing to control menopause symptoms without resorting to drugs.

The other authors were affiliated with the University of California, Davis, Oregon Health and Science University, the University of Georgia, Athens, Northern California Fertility Medical Center, and Baylor College of Medicine, Houston.

 Source: Journal of Nutrition
May 2009, Volume 139, Pages 981-986
“Various doses of soy isoflavones do not modify mammographic density in postmenopausal women”
Authors: G. Maskarinec, M. Verheus, F.M. Steinberg, P. Amato, M.K. Cramer, R.D. Lewis, M.J. Murray, R.L. Young, W.W. Wong

Targeting death receptor–mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cancer cells are intrinsically resistant to death receptor–mediated apoptosis. In an effort to identify agents that can sensitize cancer cells to death receptor–induced apoptosis, we have identified honokiol, a natural product from magnolia bark with anticancer activity, as shown in various preclinical studies, as an effective sensitizer of death receptor–mediated apoptosis. Honokiol alone moderately inhibited the growth of human lung cancer cells; however, when combined with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), greater effects on decreasing cell survival and inducing apoptosis than TRAIL alone were observed, indicating that honokiol cooperates with TRAIL to enhance apoptosis. This was also true to Fas-induced apoptosis when combined with Fas ligand or an agonistic anti-Fas antibody. Among several apoptosis-associated proteins tested, cellular FLICE-inhibitory protein (c-FLIP) was the only one that was rapidly down-regulated by honokiol in all of the tested cell lines. The down-regulation of c-FLIP by honokiol could be prevented by the proteasome inhibitor MG132. Moreover, honokiol increased c-FLIP ubiquitination. These results indicate that honokiol down-regulates c-FLIP by facilitating its degradation through a ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP abolished the ability of honokiol to enhance TRAIL-induced apoptosis. Several honokiol derivatives, which exhibited more potent effects on down-regulation of c-FLIP than honokiol, showed better efficacy than honokiol in inhibiting the growth and enhancing TRAIL-induced apoptosis as well. Collectively, we conclude that c-FLIP down-regulation is a key event for honokiol to modulate the death receptor–induced apoptosis. [Mol Cancer Ther 2008;7(7):2212–23]

ScienceDaily (Apr. 20, 2009) — An herb recently found to kill pancreatic cancer cells also appears to inhibit development of pancreatic cancer as a result of its anti-inflammatory properties, according to researchers from the Kimmel Cancer Center at Jefferson. The data were presented at the AACR 100th Annual Meeting 2009 in Denver.

Thymoquinone, the major constituent of the oil extract from a Middle Eastern herbal seed called Nigella sativa, exhibited anti-inflammatory properties that reduced the release of inflammatory mediators in pancreatic cancer cells, according to Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at the Jefferson Medical College of Thomas Jefferson University and a member of the Jefferson Pancreatic, Biliary & Related Cancers Center.

Nigella sativa seeds and oil are used in traditional medicine by many Middle Eastern and Asian countries. It helps treat a broad array of diseases, including some immune and inflammatory disorders, Dr. Arafat said. Previous studies have also shown it to have anti-cancer effects on prostate and colon cancers.

Based upon their previously published findings that thymoquinone inhibits histone deacetylases (HDACs), Dr. Arafat and her colleagues compared the anti-inflammatory properties of thymoquinone and trichostatin A, an HDAC inhibitor that has previously shown to ameliorate inflammation-associated cancers.

The researchers used pancreatic ductal adenocarcinoma (PDA) cells, some of which were pretreated with the cytokine TNF-alpha to induce inflammation. Thymoquinone almost completely abolished the expression of several inflammatory cytokines, including TNF-alpha, interleukin-1beta, interleukin-8, Cox-2 and MCP-1, an effect that was more superior to the effect of trichostatin A.

The herb also inhibited the activation and synthesis of NF-kappaB, a transcription factor that has been implicated in inflammation-associated cancer. Activation of NF-kappaB has been observed in pancreatic cancer and may be a factor in pancreatic cancer’s resistance to chemotherapeutic agents. When animal models of pancreatic cancer were treated with thymoquinone, 67 percent of the tumors were significantly shrunken, and the levels of proinflammatory cytokines in the tumors were significantly reduced.

Inflammation has been implicated in the development of several solid tumor malignancies. Chronic pancreatitis, both hereditary and sporadic, is associated with the risk of developing pancreatic cancer.

“These are very exciting and novel results,” Dr. Arafat said. “Not only patients with chronic pancreatitis could benefit from this, but also several other groups with risk of development or recurrence of pancreatic cancer, such as high-risk family members and post-surgical patients. These potent effects show promise for the herb as a potential preventive and therapeutic strategy for pancreatic cancer. More importantly, the herb and oil are safe when used moderately, and have been used for thousands of years without reported toxic effects.”

Pancreatic cancer is the fourth leading cause of cancer death in the United States, with approximately 32,000 deaths a year. Only five percent of individuals with pancreatic cancer live for at least one year after diagnosis.

ScienceDaily (Apr. 5, 2009) — Docosahexanoic acid (DHA), an omega-3 fatty acid found in fish oils, has been shown to reduce the size of tumours and enhance the positive effects of the chemotherapy drug cisplatin, while limiting its harmful side effects. The rat experiments provide some support for the plethora of health benefits often ascribed to omega-3 acids.

Professor A. M. El-Mowafy led a team of researchers from Mansoura University, Egypt, who studied DHA’s effects on solid tumours growing in mice, as well as investigating how this fatty acid interacts with cisplatin, a chemotherapy drug that is known to cause kidney damage. El-Mowafy said, “DHA elicited prominent chemopreventive effects on its own, and appreciably augmented those of cisplatin as well. Furthermore, this study is the first to reveal that DHA can obliterate lethal cisplatin-induced nephrotoxicity and renal tissue injury.”

DHA is an omega-3 fatty acid that is commonly found in cold-water fish oil, and some vegetable oils. It is a major component of brain gray matter and of the retina in most mammalian species and is considered essential for normal neurological and cellular developments. According to the authors, “While DHA has been tentatively linked with protection against cardiovascular, neurological and neoplastic diseases, there exists a paucity of research information, in particular regarding its interactions with existing chemotherapy drugs”. The researchers found that, at the molecular level, DHA acts by reducing leukocytosis (white blood cell accumulation), systemic inflammation, and oxidative stress – all processes that have been linked with tumour growth.

El-Mowafy and his colleagues have called for greater deployment of omega-3 in the fight against cancer. They write, “Our results suggest a new, fruitful drug regimen in the management of solid tumors based on combining cisplatin, and possibly other chemotherapeutics, with DHA”.

Journal reference:

1. M E Elmesery, M M Algayyar, H A Salem, M M Darweish and A M El-Mowafy. Chemopreventive and renal protective effects for docosahexaenoic acid (DHA): implications of CRP and lipid peroxides. Cell Division, (in press)

ScienceDaily (Apr. 2, 2009) — Individuals who took a dietary supplement called “factor D”, which included selenium, vitamin E, and beta-carotene, continued to have lower gastric cancer and overall mortality 10 years after supplementation ceased compared with individuals who did not take the supplements, according to long-term follow-up data from the randomized, double-blind General Population Nutrition Intervention Trial in Linxian, China.

The trial tested the impact of four dietary supplement combinations on gastric and esophageal cancer incidence and overall mortality in a nutritionally-deprived population. The trial enrolled 29,584 adults between the ages of 40 and 69 years. Participants took dietary supplements from 1986 to 1991. The initial results from the study showed a significant reduction in risk of gastric cancer and overall mortality in individuals taking factor D.

In the current analysis, Philip R. Taylor, M.D., Sc.D., of the National Cancer Institute in Bethesda, Md., and colleagues at the Chinese Academy of Medical Sciences in China examined 10-year follow-up data.

Individuals who took factor D continued to show benefits, with a 5% reduction in overall mortality (from a cumulative mortality of 33.62% of participants not taking factor D to 32.19% of participants taking factor D) and an 11% reduction in gastric cancer mortality (from a cumulative gastric cancer mortality of 4.28% in the no-factor D group to 3.84% in the factor D group). Individuals who were under the age of 55 derived the majority of benefit from the supplement. Esophageal cancer incidence decreased by 17% in participants under the age of 55, but increased by 14% in those participants over age 55.

“The persistence of risk reduction for up to 10 years after treatment in this trial reinforces the validity of the original trial findings and is consistent with an emerging new paradigm in cancer prevention, namely, that prevention may be achievable with short-term as opposed to life-long treatment,” the authors write.

The research is published in the March 24 online issue of the Journal of the National Cancer Institute

Journal reference:

1. You-Lin Qiao, Sanford M. Dawsey, Farin Kamangar, Jin-Hu Fan, Christian C. Abnet, Xiu-Di Sun, Laura Lee Johnson, Mitchell H. Gail, Zhi-Wei Dong, Binbing Yu, Steven D. Mark, and Philip R. Taylor. Total and Cancer Mortality After Supplementation With Vitamins and Minerals: Follow-up of the Linxian General Population Nutrition Intervention Trial. Journal of the National Cancer Institute, 2009; DOI: 10.1093/jnci/djp037