By Stephen Daniells, 31-Jul-2009

Using Chinese herbs either alone or in conjunction with chemotherapy may help protect a breast cancer patient’s bone marrow and immune system, as well as improving the woman’s overall quality of life.

Sixty per cent of women undergoing chemotherapy for breast cancer experience a range of significant short term side effects. These include nausea, vomiting and fatigue, as well as inflammation of the gut lining, decreased numbers of red and white blood cells and decreased numbers of blood platelets.

Chinese medicinal herbs include mixtures of herbal compounds or extracts from herbs, and they are prescribed to counteract the side effects of chemotherapy. This Cochrane Systematic Review set out to see if there is conventional evidence indicating that these medicines are safe and whether there is evidence that the medicines are effective.

The researchers identified seven randomised studies involving 542 patients with breast cancer. By analysing these data, the researchers concluded that there was no evidence that the Chinese medicinal herbal treatment caused harm, and some evidence that it might reduce side effects.

“Further trials are needed before the effects of traditional Chinese medicines for people with breast cancer can be evaluated with any real confidence,” says Assistant Professor Jing Li, who works at the Chinese Cochrane Centre in Chengdu, China.

Ginseng, one of the most widely used herbs in traditional Chinese medicine, may improve survival and quality of life after a diagnosis of breast cancer, according to a recent study by Vanderbilt-Ingram Cancer Center researchers.

Ginseng is a slow-growing perennial herb whose roots have been used in traditional Chinese medicine for more than 2,000 years. The two main classes of ginseng — red and white — have different biological effects, according to traditional Chinese medicine theory. White, or unprocessed, ginseng is used over long periods to promote general health, vitality and longevity. Red, or processed, ginseng provides a much stronger effect and is used for short periods to aid in disease recovery.

Both varieties of ginseng contain more than 30 chemicals, called ginsenosides, which have anti-tumor effects in cell culture and animal studies, suggesting that the herbs may provide specific benefits to cancer patients. In fact, ginseng use has been increasing among cancer patients in recent years, particularly in women diagnosed with breast cancer.

However, despite the encouraging laboratory findings, scientific analysis of ginseng’s health benefits in patient populations has been lacking. “There is a lot of skepticism about herbal medicine,” said Shu. “That is why we are taking the observational approach at this time to see whether there is any efficacy. If so, we can go to the next phase … and eventually go to clinical trials.”

Shu and colleagues assessed the effects of ginseng use in breast cancer survivors as part of a large epidemiological study, the Shanghai Breast Cancer Study, which has followed 1,455 breast cancer patients in Shanghai since 1996. For the current study, Shu and colleagues evaluated breast cancer patients for ginseng use both before and after their diagnosis of breast cancer. All patients who used ginseng had received at least one type of conventional cancer therapy (e.g., surgery, chemotherapy and/or radiotherapy).

Information on ginseng use prior to cancer diagnosis, which was available for every subject, was used to determine whether prior ginseng use predicted survival. At follow up — about three to four years after diagnosis — the researchers asked about ginseng use since diagnosis. That information, which was available only for survivors, was used to look at quality of life measurements — i.e., physical, psychological, social and material well-being.

Before diagnosis, about a quarter of patients (27.4 percent) reported using ginseng regularly. After diagnosis, that percentage jumped to 62.8 percent, the researchers found. They also found significant improvements in both survival and quality of life measures in patients who used ginseng. “When patients used ginseng prior to diagnosis, they tended to have higher survival,” Shu explained. “Ginseng use after cancer diagnosis was related to improved quality of life.”

The findings suggest that ginseng may provide tangible benefits to breast cancer survivors, but there are limitations to the study. The varieties and the methods of ginseng use and the use of other complementary and alternative therapies could not be fully accounted for in the analysis. Also, the quality of life measures exclusively relied on patient self-reporting.

Although side effects of ginseng use were not recorded in this study, Shu warned that the seemingly innocuous root can create problems when improperly used and should be taken with caution. “It’s not a ‘drug’ in terms of being managed by the FDA, but it was used as a drug in traditional Chinese medicine,” she said. “Any drug may have some side effects and may interact with other drugs. So, discuss with your primary care doctor before you decide to take ginseng roots or products.”

Shu hopes to confirm and expand the current findings through continued collection of data in this patient population, from another ongoing study of 4,000 breast cancer patients, and eventually, in randomized clinical trials. Scientific study of complementary and alternative medicines is tricky though, said Shu. “Chinese traditional medicine is very individualized. It gives you different drugs based on your symptoms and your overall health. There is much to be learnt.”

 The large epidemiological study, led by Xiao-Ou Shu, M.D., Ph.D., was published online recently in the American Journal of Epidemiology.

Other authors on the paper were Yong Cui, M.D., Hui Cai, M.D., Ph.D., Meng-Hua Tao, M.D., and Wei Zheng, M.D., Ph.D., from Vanderbilt and Yu-Tang Gao, M.D., from the Shanghai Cancer Institute. The research was supported by grants from the National Cancer Institute.

ScienceDaily (Apr. 24, 2009) — Researchers at Lombardi Comprehensive Cancer Center at Georgetown University Medical Center have demonstrated that naturally-occurring compounds can selectively deplete mutant p53 and restore “wild type” function to p53 in a variety of tumor cells.

Mutations in the p53 tumor suppressor gene – which is involved in apoptosis and DNA repair – occur in about half of all human tumors. p53 often acts as a checkpoint preventing abnormal cells from continuing to grow and divide. However mutations in p53 gene are one way that pre-cancerous cells overcome normal cellular controls and replicate without restraint.

This study demonstrates for the first time that phenethyl isothiocyante (PEITC), a naturally-occurring compound, can selectively deplete mutant p53. The authors also made an intriguing observation that the depletion of mutant p53 in human cancer cells is accompanied by restoration of the wild type p53. PEITC is a member of the isothiocyanate family compounds found in cruciferous vegetables, such as watercress, broccoli and cabbage. PEITC has been shown to have cancer preventive activity.

The researchers found that PEITC not only decreases the level of mutated p53 protein in tumor cells, but also restores the “wild type” or normal activity to mutated p53. The effect of this is that tumor cell lines with mutant p53 became more sensitive to PEITC-induced cytotoxicity than tumor cells with wild type p53, suggesting that the normal p53 checkpoint control pathways have been restored in the mutant p53-expressing tumor cells. This novel finding suggests that the PEITC and other compounds in the isothiocyante family could play important role in both cancer prevention and treatment of human cancers with mutant p53.

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.

BACKGROUND:
Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with seven botanicals purported to have immune stimulant effects.

METHODS:
Groups of 5-10 mice were immunized with globo H-KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. three times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested:
(1) H-48 (Honso USA Co.), (2) Coriolus versicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co. Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast beta-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semisynthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH.

RESULTS:
Consistent significant adjuvant activity was observed after s.c. vaccination with the Coriolus extracts (especially PSK), a 95% ethanol extract of Astragalus and yeast beta-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H-48 or Echinacea extracts or the Astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast beta-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in Astragalus, it had no impact on Coriolus where the 90% ethanol precipitate and solute were equally active.

CONCLUSIONS:
Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and Astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components.

Author information

Author/s: Ragupathi, Govind (G); Yeung, K Simon (KS); Leung, Ping-Chung (PC); Lee, Mavis (M); Lau, Clara Bik San (CB); Vickers, Andrew (A); Hood, Chandra (C); Deng, Gary (G); Cheung, Nai-Kong (NK); Cassileth, Barrie (B); Livingston, Philip (P);

Affiliation: Laboratory of Tumor Vaccinology, Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. ragupatg(-atsign-)mskcc.org

Grants: 1 P50 AT002779-01 (Agency:NCCAM NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t

Journal: Vaccine (Vaccine), published in Netherlands. (Language: eng)

Reference: 2008-Sep; vol 26 (issue 37) : pp 4860-5

Dates: Created 2008/08/25; Completed 2008/10/15;

PMID: 18640165, status: MEDLINE (last retrieval date: 2/18/2009)

Zhuang SR, Chen SL, Tsai JH, Huang CC, Wu TC, Liu WS, Tseng HC, Lee
HS, Huang MC, Shane GT, Yang CH, Shen YC, Yan YY, Wang CK. Phytother
Res. 2009 Jan 14

Leukopenia and immunity impairment usually occur during cancer therapy.

This randomized, double-blind, placebo-controlled study examined whether the Chinese medicinal herb complex (CCMH; a mixture of citronellol and extracts of G. lucidum, C. pilosula and A. sinensis) improves the immune cell counts of cancer patients receiving chemotherapy and/or radiotherapy.

Citronellol, an oil soluble compound derived from the geranium, has anticancer and antiinflammatory properties, as well as promoting wound healing.

Ganoderma lucidum, Codonopsis pilosula and Angelicae sinensis are TCM herbs, all of which have proven immunomodulatory functions in laboratory-based research.

A total of 105 cancer patients receiving chemotherapy or radiotherapy were enrolled. The quantities of immune cells in the blood of the subjects were determined before and after 6 weeks of cancer treatment, with either CCMH or a placebo. CCMH significantly reduced the depletion of leukocytes (14.2% compared with 28.2%) and neutrophils (11.0% compared with 29.1%). Analysis of the lymphocyte phenotype revealed that the patients receiving the placebo had reduced CD4 lymphocytes and natural killer (NK) cells than the CCMH-treated patients.

Treatment with CCMH for patients receiving chemotherapy and/or radiotherapy may improve their immune function, improving their ability to fight off the cancer, as well as any secondary infections that could compromise their treatment and their health.

Sagar SM, Yance D, Wong RK. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer – Part 2. Current Oncology. 2008;13(1): 1-9.

The authors recap conclusions from Part 1 (HC 070483-366):  By targeting multiple biologic pathways, multi-compound botanicals may inhibit angiogenesis more effectively than single-compound chemotherapeutic agents, arousing less resistance and reducing compensation for decreased activity on one pathway by increased activity on another. By using whole herbs and combining botanicals as traditional practice dictates, a therapeutic advantage may be gained.

Vascular endothelial growth factor (vegf), hepatocyte growth factor (hgf), leptin, tumor necrosis factor alpha (tnfα), heparin-binding epidermal growth factor, insulin-like growth factor, and interleukin-6 (il-6) are associated with obesity, hyperinsulinemia, chronic vascular disease, and cancer, as well as promoting angiogenesis. Aminopeptidase-D (cd13) is involved in the switch between active angiogenesis and resolution in normal cells turned on permanently by tumors. Other angiogenic pathways include production of transforming growth factor beta (tgfβ); amplification of cyclooxygenase-2 (cox-2), epidermal growth factor receptor (egfr), and nuclear factor kappa-B (nf-kb) signaling. Curcumin from turmeric (Curcuma longa), epigallocatechin-3-gallate (egcg) from green tea (Camellia sinensis), and resveratrol and proanthocyanidins from grape (Vitis spp.) seed exert effects at several levels to suppress inflammatory, hyperproliferative, and transformative processes that define carcinogenesis.

Aggressive cancer, resistance, and poor prognosis are associated with over-expression of egfr, which induces angiogenesis. Monoclonal antibodies are used to block the receptor or its signaling system. Epidermal growth factor (egf) stimulates urokinase-type plasminogen activator (upa), an angiogenesis promoter. Genistein, found in soy (Glycine max), and curcumin both inhibit egf’s effects and inhibit tyrosine kinases, which raise upa levels induced by tgfβ. Other botanicals that block egfr activity are resveratrol and quercetin. The her2/neu gene, amplified in over 30% of patients with breast cancer, is linked to aggressive tumors and poor prognosis and over-expressed in many cancers. Higher her2 levels correlate with more angiogenesis. Herceptin™ (Genentech, San Francisco, CA), a her2 inhibitor, may be enhanced by oleic acid from olives (Olea europaea). Emodin, in Chinese knotweed (Polygonum multiflorum) and aloe (Aloe vera), inhibits her2 and kills cancer cells.

Prostaglandins cox-2 and lipoxygenase (lox-5), products of omega-6 fatty acid’s metabolism, stimulate cancer progress and angiogenesis. Omega-3 fatty acids, found in fish oils, flax (Linum usitatissimum) seed, and hemp (Cannabis sativa) seed, antagonize these effects. Glycyrrhizic acid and polyphenols from licorice (Glycyrrhiza glabra) inhibit cox-2, lox-5, and protein kinase C (pkc) and down regulate egf. nf-kb, amplified by growth factors and other transcription factors such as activator protein-1 (ap-1) and il-6, stimulate cox-2 transcription. ap-1 also promotes metastasis. cox-2-mediated angiogenesis contributes to progression of pre-neoplastic lesions. Conventional therapies may induce cox-2. Phytochemical inhibitors of nf-kb include egcg; resveratrol; piceatannol, a derivative of resveratrol found in peanut (Arachis hypogaea) calluses and grapes; curcumin; 6-gingerol from ginger (Zingiber officinale); ursolic acid from holy basil (Ocimum sanctum); and ginseng (Panax ginseng).

In normal cells, protein kinases are part of the signaling system regulating cell cycles. Mutated kinase genes contribute to cancer development, forcing cells to constantly divide. egfr is a kinase commonly overproduced in cancer. Phytochemicals that interfere with cell signaling may reverse effects of kinase over activity; some also inhibit cox-2. Carnosol reduces nf-kb and excess signaling protein Bel-2. Genistein and daidzein from soy inhibit tyrosine kinases. Curcumin, vitamin E, catechins from green tea, resveratrol, reishi mushroom (Ganoderma lucidum), and licorice inhibit pkc. Signaling protein Bel-2 normally releases cytochrome C, triggering enzymes that lead to apoptosis. Excess Bel-2 blocks cytochrome C and appears to contribute to inherent and acquired resistance. bcl2 and tp53 genes regulate vegf-mediated angiogenesis. Curcumin and green tea extract inhibit bcl2. Chinese skullcap’s (Scutellaria baicalensis) phenolic compounds inhibit bcl2 and cox-2 expression and nf-kb activation. Protocatechuic acid from hibiscus (Hibiscus sabdariffa) flower inhibits Bel-2 activity. In some trials, anticoagulation drugs are associated with reduced metastases. In Traditional Chinese Medicine, destagnation herbs are used to unblock qi and blood, and evidence suggests they may have anticoagulant and anti-angiogenic effects. Among those showing positive results when used with radiation therapy are dan shen (Salvia miltiorrhiza) and dong quai (Angelica sinensis).

Most natural anti-angiogenics are cytostatic rather than cytotoxic, necessitating a change in the drug development paradigm away from tumor response to other indicators. Potential side effects, e.g. ulceration and bleeding, must be studied. Dosing and scheduling remain unclear.

Reference