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

ScienceDaily (Jan. 1, 2009) — An extract from grape seeds forces laboratory leukemia cells to commit cell suicide, according to researchers from the University of Kentucky. They found that within 24 hours, 76 percent of leukemia cells had died after being exposed to the extract.

The investigators, who report their findings in the January 1, 2009, issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, also teased apart the cell signaling pathway associated with use of grape seed extract that led to cell death, or apoptosis. They found that the extract activates JNK, a protein that regulates the apoptotic pathway.

While grape seed extract has shown activity in a number of laboratory cancer cell lines, including skin, breast, colon, lung, stomach and prostate cancers, no one had tested the extract in hematological cancers nor had the precise mechanism for activity been revealed.

“These results could have implications for the incorporation of agents such as grape seed extract into prevention or treatment of hematological malignancies and possibly other cancers,” said the study’s lead author, Xianglin Shi, Ph.D., professor in the Graduate Center for Toxicology at the University of Kentucky.

“What everyone seeks is an agent that has an effect on cancer cells but leaves normal cells alone, and this shows that grape seed extract fits into this category,” he said.

Shi adds, however, that the research is not far enough along to suggest that people should eat grapes, grape seeds, or grape skin in excess to stave off cancer. “This is very promising research, but it is too early to say this is chemo-protective.”

Hematological cancers – leukemia, lymphoma and myeloma – accounted for an estimated 118,310 new cancer cases and almost 54,000 deaths in 2006, ranking these cancers as the fourth leading cause of cancer incidence and death in the U.S.

Given that epidemiological evidence shows that eating vegetables and fruits helps prevent cancer development, Shi and his colleagues have been studying chemicals known as proanthocyanidins in fruits that contribute to this effect. Shi has found that apple peel extract contains these flavonoids, which have antioxidant activity, and which cause apoptosis in several cancer cell lines but not in normal cells. Based on those studies, and findings from other researchers that grape seed extract reduces breast tumors in rats and skin tumors in mice, they looked at the effect of the compound in leukemia cells.

Using a commercially available grape seed extract, Shi exposed leukemia cells to the extract in different doses and found the marked effect in causing apoptosis in these cells at one of the higher doses.

They also discovered that the extract does not affect normal cells, although they don’t know why.

The researchers then used pharmacologic and genetic approaches to determine how the extract induced apoptosis. They found that the extract strongly activated the JNK pathway, which then led to up-regulation of Cip/p21, which controls the cell cycle.

They checked this finding by using an agent that inhibited JNK, and found that the extract was ineffective. Using a genetic approach – silencing the JNK gene – also disarmed grape seed extract’s lethal attack in leukemia cells.

“This is a natural compound that appears to have relatively important properties,” Shi said.

ScienceDaily (Jan. 10, 2009) — Researchers from the University of Granada and the University of Barcelona have shown that treatment with maslinic acid, a triterpenoid compound isolated from olive-skin pomace, results in a significant inhibition of cell proliferation and causes apoptotic death in colon-cancer cells. Maslinic acid is a novel natural compound and it is able to induce apoptosis or programmed death in human HT29 colon-cancer cells via the intrinsic mitochondrial pathway.

New research suggest this could be a useful new therapeutic strategy for the treatment of colon carcinoma.

This study is the first to investigate the precise molecular mechanisms of the anti-tumoral and pro-apoptotic effects of maslinic acid against colon-cancer. Chemopreventive agents of a natural origin, often a part of our daily diet, may provide a cheap, effective way of controlling such diseases as cancer of the colon. A wide range of studies in recent years has shown that triterpenoids hinder carcinogenesis by intervening in pathways such as carcinogen activation, DNA repair, cell cycle arrest, cell differentiation and the induction of apoptosis in cancer cells.

Triterpenoids are compounds present in a wide range of plants used in traditional medicine and known to have antitumoral properties. Low concentrations of maslinic acid are to be found in plants with medicinal properties, but its concentration in the waxy skin of olives may be as high as 80%.

The results of the study could contribute to the development of maslinic acid for use as cancer chemotherapeutic or chemopreventive agents.

Journal reference:

1. Reyeszurita et al. Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Letters, 2009; 273 (1): 44 DOI: 10.1016/j.canlet.2008.07.033