Eric Yarnell, ND, RH(AHG)

“Perhaps the most important advance in this field is not the specific actions of all-trans-retinoic acid in acute promyelocytic leukemia, but rather the conclusive documentation of differentiation as a practical and consistently effective method of treating human cancer.” – Warrell et al. (1993)

One of the hallmarks of cancer is that the affected cells dedifferentiate. To varying degrees, cancer cells become more primitive, losing normal functions in the process. While for a very long time it was not believed in mainstream medicine that cancer could revert to normal, it is now recognized as readily achievable, as noted in the introductory quote.

Botanical medicines offer many tools to promote redifferentiation, and thus may help patients recover from cancer. This article will review a few promising agents in this area.

Panax ginseng (Asian ginseng)

Reports about the ability of Asian ginseng or its various ginsenosides to induce differentiation in experimental systems have been published since the 1970s (Odashiam et al., 1979). Crude extracts of Asian ginseng or specific ginsenosides, notably Rh1 and Rh2, have repeatably caused differentiation in vitro of melanoma, teratocarcinoma, hepatoma and leukemia cells (Odashima et al., 1989; Lee et al., 1996; Xia and Han, 1996; Kim et al., 1998). Some research on the mechanism of how ginsenosides can induce differentiation concluded it was through direct interaction with the glucocorticoid receptor (Lee et al., 1998).

Clinical trials of Asian ginseng and cancer patients are limited. One brief trial found improvement in some symptoms in cancer patients (Kim et al., 2006). A larger trial found that Asian ginseng polysaccharides combined with radiation therapy were significantly more effective at prolonging life, preventing metastasis and reducing symptoms in Chinese patients with nasopharyngeal cancer compared to standard allopathic treatment (Xie et al., 2001). While no clinical trial to date has proven that Asian ginseng in any form has a redifferentiating effect in human cancer patients, Asian ginseng can be reasonably used by clinicians, given its long history and safety. Typical doses are 5-10g daily of the root or equivalent extracts.

Complex Carbohydrates

Many anti-cancer herbs contain complex polysaccharides, well documented to have immunomodulating effects in cancer patients. It is now becoming clear that these compounds can also have redifferentiating effects. Rice polysaccharides, for example, have been shown to induce differentiation in leukemia cells (Liao et al., 2006). Redifferentiation was associated with leukocyte activity in this study, suggesting that the differentiating effects of polysaccharides may be a downstream result of immunomodulation.

Notable immunomodulating herbs with polysaccharides long used in traditional Asian medicine for cancer that have shown redifferentiating effects are the fungi Poria cocos (fu-ling, hoelen) and Cordyceps sinensis (Chen and Chang, 2004; Chen et al., 1997). In both of these studies, the redifferentiation appeared to be due to changes in cytokine levels. Clinical trials are warranted to determine if polysaccharides induce differentiation in humans; their benefits for lengthening life span in cancer patients are already well established (Kidd, 2000).

Short Chain Fatty Acids

Short chain fatty acids, such as butyrate, are formed by digestion of complex polysaccharides by normal colon flora. These compounds may explain, in part, the action of complex polysaccharides from herbs in differentiation therapy. Butyrate in particular has been shown to have potent redifferentiating effects on various cancer cells in vitro, and acts synergistically with retinoids (Breitman and He, 1990). Human promyelocytic leukemia cell lines have been shown to be redifferentiated by butyrate, both alone and in combination with niacin and retinoids (Merzvinskyte et al., 2006). A very recent study found butyrate could induce differentiation in colon cancer cells (Yamane and Yamane, 2007).

Patients with colon adenomas have been shown to have low baseline fecal butyrate levels (Boutron-Ruault, et al., 2005). Administration of short-chain fructo-oligosaccharides in these patients raised butyrate levels and had a modest beneficial effect on improving bile acid makeup. Administration of pivaloyloxymethyl butyrate, a drug version of butyrate, in preliminary clinical trials has been associated with significant lifespan benefits in patients with non-small-cell lung cancer (Reid et al., 2004). Clearly, much more work is needed, but these preliminary findings support the use of either fiber-rich foods or butyrate supplements as safe redifferentiation therapy.

A combination of redifferentiating natural products should be considered in any patient with aggressive or metastatic cancer, to further increase the odds of their improving or living as long and as well as possible. Further research is needed to verify the efficacy and safety of this addition to treatment.

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Eric Yarnell, ND, RH(AHG) is a graduate of Bastyr University. He completed a two-year residency with Silena Heron, ND, and served as chair of botanical medicine at SCNM. He is past senior editor of the Journal of Naturopathic Medicine. Dr. Yarnell is a founding member and current president of the Botanical Medicine Academy and author of numerous textbooks and articles, including Naturopathic Urology and Men’s Health, Naturopathic Gastroenterology and Clinical Botanical Medicine. His area of clinical focus is urology and men’s health. He is assistant professor in botanical medicine at Bastyr University.

 

References

Boutron-Ruault MC et al: Effects of a 3-mo consumption of short-chain fructo-oligosaccharides on parameters of colorectal carcinogenesis in patients with or without small or large colorectal adenomas, Nutr Cancer 53(2):160-8, 2005.

Breitman TR, He RY: Combinations of retinoic acid with either sodium butyrate, dimethyl sulfoxide, or hexamethylene bisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL60, Cancer Res 50:6268-73, 1990.

Chen YY, Chang HM: Antiproliferative and differentiating effects of polysaccharide fraction from fu-ling (Poria cocos) on human leukemic U937 and HL-60 cells, Food Chem Toxicol 42(5):759-69, 2004.

Chen YJ et al: Effect of Cordyceps sinensis on the proliferation and differentiation of human leukemic U937 cells, Life Sci 60(25):2349-59, 1997.

Kidd PM: The use of mushroom glucans and proteoglycans in cancer treatment, Alt Med Rev 5:4-27, 2000.

Kim YS et al: Ginsenoside Rh2 and Rh3 induce differentiation of HL-60 cells into granulocytes: modulation of protein kinase C isoforms during differentiation by ginsenoside Rh2, Int J Biochem Cell Biol 30(3):327-38, 1998.

Kim JH et al: Effects of sun ginseng on subjective quality of life in cancer patients: a double-blind, placebo-controlled pilot trial, J Clin Pharm Ther 31(4):331-4, 2006.

Lee YN et al: In vitro induction of differentiation by ginsenoides [sic] in F9 teratocarcinoma cells, Eur J Cancer 32A(8):1420-8, 1996.

Lee YN et al: Involvement of glucocorticoid receptor in the induction of differentiation by ginsenosides in F9 teratocarcinoma cells, J Steroid Biochem Mol Biol 67(2):105-11, 1998.

Liao HF et al: Rice (Oryza sativa L.) inhibits growth and induces differentiation of human leukemic U937 cells through activation of peripheral blood mononuclear cells, Food Chem Toxicol 44(10):1724-9, 2006.

Merzvinskyte R et al: Effects of histone deacetylase inhibitors, sodium phenyl butyrate and vitamin B3, in combination with retinoic acid on granulocytic differentiation of human promyelocytic leukemia HL-60 cells, Ann N Y Acad Sci 1091:356-67, 2006.

Odashima S et al: Induction of phenotypic reverse transformation by plant glycosides in cultured cancer cells (in Japanese), Gan To Kagaku Ryoho 16(4 Pt 2-2):1483-9, 1989.

Odashima S et al: Induction of phenotypic reverse transformation by ginsenosides in cultured Morris hepatoma cells, Eur J Cancer 15(6):885-92, 1979.

Reid T et al: Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer, Lung Cancer 45(3):381-6, 2004.

Warrell RP et al: Acute promyelocytic leukemia, N Engl J Med 329:177-89, 1993.

Xia LJ, Han R: Differentiation of B16 melanoma cells induced by ginsenoside RH2 (in Chinese), Yao Xue Xue Bao 31(10):742-5, 1996.

Xie FY et al: Clinical observation on nasopharyngeal carcinoma treated with combined therapy of radiotherapy and ginseng polysaccharide injection (in Chinese), Zhongguo Zhong Xi Yi Jie He Za Zhi 21(5):332-4, 2001.

Yamane M, Yamane S: The induction of colonocyte differentiation in CaCo-2 cells by sodium butyrate causes an increase in glucosylceramide synthesis in order to avoid apoptosis based on ceramide, Arch Biochem Biophys 459(2):159-68, 2007.

 

SIDEBAR 1: Box out

Miscellaneous Natural Redifferentiation Agents

• Artemisia annua (sweet Annie) leaf and artemisinin
• Berberbis spp (barberry), Mahonia aquifolium (Oregon grape) and related plants containing berberine-family isoquinoline alkaloids
• Resveratrol
• 9-cis Retinoic acid (natural vitamin A)
• Stephania tetrandra (stephania) root
• Vitamin D3, 1,25-dihydroxyvitamin D3