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Research Information - Dog Cancer & Arthritis Treatment Options - Curcumin



Introduction

According to the National Cancer Institute, curcumin is a phytopolylphenol pigment isolated from the plant Curcuma longa, commonly known as tumeric, with a variety of pharmacologic properties. Curcumin blocks the formation of reactive-oxygen species, possesses anti-inflammatory properties as a result of inhibition of cyclooxygenases (COX) and other enzymes involved in inflammation; and disrupts cell signal transduction by various mechanisms including inhibition of protein kinase C. These effects may play a role in the agent's observed antineoplastic properties, which include inhibition of tumor cell proliferation and suppression of chemically induced carcinogenesis and tumor growth in animal models of cancer.

In the book, Prescription for Herbal Healing, curcumin is noted as causing the death of cancer cells arising from several different types of tissue. By curtailing the activity of platelet-activating factor (PAF), which is necessary for the formation of new blood vessels that tumors need to grow, curcumin can keep tumors from spreading. Curcumin can also aid recovery from cancer by stimulating the immune system. In Dr. Kidd's Guide to Herbal Dog Care, he believes tumeric to have anticancer properties, anti-inflammatory properties, antimicrobial characteristics, cardiovascular system benefits (inhibits platelet aggregation and interferes with intestinal cholesterol uptake), and intestinal benefits (decreases gas formation). He believes it is the perfect herb to sprinkle on your dog's food, as dogs relish its taste.

Turmeric Root (Curcuma longa). Adding curcumin, the active substance found in turmeric, to human cells with the blood cancer multiple myeloma, Dr. Bharat B. Aggarwal of the University of Texas MD Anderson Cancer Center in Houston and his colleagues, not only stopped cancer cells from replicating but also killed the cells that were left.

Mayo Clinic medical oncologist Timothy Moynihan, M.D. states that "Curcumin is thought to have antioxidant properties, which means it may decrease swelling and inflammation. It's being explored as a cancer treatment because inflammation appears to play a role in cancer. Lab research suggests that curcumin may slow the spread of cancer and the growth of new tumor blood vessels. It may also cause cancer cells to die. In the lab, curcumin has been studied for use in treating or preventing colon, skin and breast cancers."

Article on Artemisinin and cancer for general information (from Science Daily, October 30, 2006)

ScienceDaily (Oct. 30, 2006) - An ancient spice, long used in traditional Asian medicine, may hold promise for the prevention of both rheumatoid arthritis and osteoporosis, according to a recently completed study at The University of Arizona College of Medicine.

Turmeric, the spice that flavors and gives its yellow color to many curries and other foods, has been used for centuries by practitioners of Ayurvedic medicine to treat inflammatory disorders. Turmeric extract containing the ingredient curcumin is marketed widely in the Western world as a dietary supplement for the treatment and prevention of a variety of disorders, including arthritis.

At the UA College of Medicine, Janet L. Funk, MD, working with Barbara N. Timmermann, PhD, then-director of the National Institutes of Health (NIH)-funded Arizona Center for Phytomedicine Research at the UA, set out to determine whether (and how) turmeric works as an anti-arthritic. They began by preparing their own extracts from the rhizome, or root, of the plant, providing themselves with well-characterized materials to test and to compare with commercially available products. (Dr. Timmermann since has joined the faculty of the University of Kansas, Lawrence, Kan.)

Dr. Funk and her colleagues then tested in animal models a whole extract of turmeric root, only the essential oils, and an oil-depleted extract containing the three major curcuminoids found in the rhizome. Of the three extracts, the one containing the major curcuminoids was most similar in chemical composition to commercially available turmeric dietary supplements. It also was the most effective, completely inhibiting the onset of rheumatoid arthritis.

Dr. Funk, an endocrinologist in the UA Department of Medicine, says this study provides several noteworthy "firsts." Completed with the researchers' own prepared, well-defined extracts, the study represents the first documentation of the chemical composition of a curcumin-containing extract tested in a living organism, in vivo, for anti-arthritic efficacy. It also provides the first evidence of anti-arthritic efficacy of a complex turmeric extract that is analogous in composition to turmeric dietary supplements.

The significance, she explains, is that translating the results of trials such as these to clinical use depends on accurate information about the chemical content and biological activity of the botanical supplements available for use. This work paves the way for the preclinical and clinical trials needed before turmeric supplements can be recommended for medicinal use in preventing or suppressing rheumatoid arthritis.

This study also provides the first in vivo documentation of a mechanism of action -- how curcumin-containing extracts protect against arthritis. The researchers found that the curcuminoid extract inhibits a transcription factor called NF-KB from being activated in the joint. A transcription factor is a protein that controls when genes are switched on or off. Once the transcription factor NF-KB is activated, or turned on, it binds to genes and enhances production of inflammatory proteins, destructive to the joint. The finding that curcuminoid extract inhibits activation of NF-KB suggests that turmeric dietary supplements share the same mechanism of action as anti-arthritic pharmaceuticals under development that target NF-KB. It also suggests that turmeric may have a use in other inflammatory disorders, such as asthma, multiple sclerosis and inflammatory bowel disease.

In addition to preventing joint inflammation, Dr. Funk's study shows that the curcuminoid extract blocked the pathway that affects bone resorption. Noting that bone loss associated with osteoporosis in women typically begins before the onset of menopause, she has begun work on another NIH-funded study to determine whether turmeric taken as a dietary supplement during perimenopause can prevent bone loss and osteoporosis. Both of the studies are supported by the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS), both of the NIH.

An initial publication of the rheumatoid arthritis study results in the Journal of Natural Products, which was among the most-accessed articles from April-June 2006 in this prestigious American Chemical Society journal, is being followed by more detailed study results, which will appear in the November 2006 issue of the American College of Rheumatology flagship journal, Arthritis and Rheumatism. The article, "Efficacy and Mechanism of Action of Turmeric Supplements in the Treatment of Experimental Arthritis," is scheduled to appear in the online issue of Arthritis and Rheumatism Monday, Oct. 30, 2006.

Contributors to the study include Janet L. Funk, MD; Jennifer B. Frye; Janice N. Oyarzo, MS; Nesrin Kuscuoglu, PhD; Jonathan Wilson; Gwen McCaffrey, PhD; Gregory Stafford; Guanjie Chen, MD; R. Clark Lantz, PhD; Shivanand D. Jolad, PhD; Aniko M. Soělyom, PhD; Pawel R. Kiela, DVM, PhD; and Barbara N. Timmermann, PhD.

Dr Dressler DVM......"Curcumin is found in turmeric, which is the spice that is used in curries. Curcumin is exceedingly interesting for dogs with cancer. It is one of the core ingredients I use in cancer supplement programs for my patients and I have seen literal shrinkage of different dog lumps, like hemangiosarcomas of the skin, fatty tumors (lipomas) , fibrosarcomas, and plasmacytomas. I rely on it a lot. This substance is being used as a model for tons of anticancer drugs in development right now. Over 40 different curcumin analogs (new drugs using curcumin as a template) are being researched at Ohio State University.{Dr Dressler}'

Published Article by Narda G. Robinson, DO, DVM, MS, FAAMA

It sounds like the ideal cancer chemopreventive - natural, safe, well-tolerated, and effective. Curcumin, from the familiar spice turmeric, has served as a traditional treatment for thousands of years for skin wounds, inflammation, and tumors (i). Now it has gained the attention of contemporary investigators as in "Curcumin appears to possess all the desirable features of a desk-designed, multipurpose drug" (ii) and, "No natural agent has yet been described which modulates so many signal transduction pathways as curcumin does." (iii) M.D. Anderson Cancer Center researchers offered, "From numerous studies, it is quite apparent that curcumin has tremendous potential for prevention and therapy of various cancers." (iv).

How It Works

Cancer cells employ multiple pathways to evade host defenses, so a drug or plant compound that attacks cancer in heterogeneous ways offers unique advantages, especially when it completes this mission relatively risk-free. In its interaction with several cellular proteins, curcumin antioxidates, induces phase II detoxification enzymes, suppresses tumor cell proliferation in several cancer cell lines, and down-regulates transcription factors (NF-?B, AP-1, Egr-1). It down-regulates enzymes such as cyclo-oxygenase-2 (COX-2), lipo-oxygenase (LOX), nitric oxide synthase (NOS), matrix metalloproteinase 9, urokinase-type plasminogen activator, and more. Curcumin also down-regulates other factors and receptors such as tumor necrosis factor, chemokines, cell surface adhesion molecules, and growth factor receptors (e.g., EGFR, HER2). Curcumin acts antiangiogenically and enhances the cytotoxicity of certain chemotherapy drugs.

Curcumin causes cell death in several human cancer cell lines, including breast, lung, prostate, colon, melanoma, kidney, hepatocellular, ovarian, leukemia. The effect curcumin has on cell death involves both the usual apoptotic mechanisms such as oligonucleosomal DNA degradation and alternative means. That is, when resistance develops to apoptosis-inducing factors, curcumin can overcome this impediment through alternative cell-signaling pathways such as mitotic catastrophe (v). Mitotic catastrophe involves a morphologically distinct and aberrant mitotic process that distinguishes it from apoptosis, characterized by the formation of giant, multinucleated cells carrying uncondensed chromosomes. Curcumin may also counteract the induction of pro-survival factors in cells generated by radiation therapy and chemotherapy.

Beyond Cancer

Curcumin's versatility allows it to help with conditions other than cancer. Two studies from India indicate that topical turmeric helps control dermatomycoses and bacterial dermatitis. (vi) Curcuminoids act synergistically against Toxocara canis. (vii) A randomized, double-blind, placebocontrolled parallel group trial of turmeric in dogs with osteoarthritis showed a statistically significant treatment effect for curcumin (known in this study as P54FP) according to investigator assessment. (viii) Curcumin inhibits proliferation of human retinal endothelial cells exposed to high glucose levels likely by affecting vascular endothelial growth factor (VEGF), and thus may forestall diabetic retinopathy. (ix) The antioxidants found in curcumin increase the life span of experimental animals, offset senescent immune decline, and protect the function of mitochondria. (x) Curcumin inhibits glutamate-mediated excitotoxicity and prevents the pathogenic aggregation of proteins that typically occur in neurodegenerative conditions such as Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, and Friedrich's ataxia. It limits lipid peroxidation and the accumulation of substances such as lipofuscin and betaamyloid, associated with cognitive impairments. In fact, researchers are now studying this agent in Phase II clinical trials on patients with mild to moderate Alzheimer's disease.

Safe at any dose?

Human clinical trials demonstrate no dose-limiting toxicity when given up to 10 g of curcumin in one day. (xi) The amount of curcumin contained in turmeric averages only about 3% by weight (xii); concentrated curcumin supplements therefore supposedly provide higher levels of the active constituent, provided that the label and actual contents agree. The hurdles of gaining and maintaining adequate blood levels of curcumin pertain to its low bioavailability outside of the gastrointestinal tract, although absorption varies between species. (xiii) One way to overcome delivery challenges could include coupling it with compounds that focus curcumin's activity toward specific target cells.

Herb-Drug interactions

In that it affects so many pathways, curcumin could hypothetically negate some of the effects of chemotherapy. Certain reports suggest that curcumin can inhibit chemotherapy-induced apoptosis in breast cancer cells specifically in combination with camptothecin, mechlorethamine, or doxorubicin.

Other Dietary Chemopreventives

Several foodstuffs offer chemoprevention. The main polyphenol in green tea, epigallocatechin-3-gallate (EGCG), induces apoptosis and promotes cell growth arrest. (xiv) Apigenin, found at high levels in peppermint, parsley, and thyme, possesses antioxidant, anti-tumor, and antiinflammatory activities. However, "not all antioxidants are created equal" and antioxidant mixtures can potentially either undo or augment one another, due to their sometimes antagonist or synergistic mechanisms of action. (xv) Food-sourced cancer-fighters thus provide an ongoing bounty of fruitful investigational arenas.

References

  1. Cuendet M and Pezzuto JM. The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. COX andLOX in Cancer Prevention. 2000;17(1-4); 109-157.
  2. Salvioli S, Sikora E, Cooper EL, et al. Curcumin in cell death processes: a challenge for CAM of age-related pathologies. eCAM. 2007;4(2):181-190.
  3. Aggarwal BB, Kumar A, and Bharti AC. Review. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research. 2003;23:363-398.
  4. Aggarwal BB, Kumar A, and Bharti AC. Review. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research. 2003;23:363-398.
  5. Salvioli S, Sikora E, Cooper EL, et al. Curcumin in cell death processes: a challenge for CAM of age-related pathologies. eCAM. 2007;4(2):181-190.
  6. Attri A, Rajora VS, Gupta DK, et al. Therapeutic efficacy of topical herbal formulation against dermatomycoses and bacterioal dermatitis in dogs. Indian J Vet Med. 2005;25(1):51-52.
  7. Kiuchi F, Goto Y, Sugimoto N, et al. Nematocidal activity of turmeric: synergistic action of curcuminoids. Chem Pharm Bull. 1993;41(9):1640-1643.
  8. Innes JF, Fuller CJ, Grover ER, et al. Randomised, double-blind, placebo-controlled parallel group study of P54FP for the treatment of dogs with osteoarthritis. Veterinary Record. 2003;152:457-460.
  9. Rema M and Pradeepa R. Diabetic retinopathy: an Indian perspective. Indian J Med Res. 2007;125:297-310.
  10. Miquel J, Bernd A, Sempere JM, et al. The curcuma antioxidants: pharmacological effects and prospects for future clinical use. A review. Archives of Gerontology and Geriatrics. 2002;34:37-46.
  11. Aggarwal BB, Kumar A, and Bharti AC. Review. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research. 2003;23:363-398.
  12. Tayyem RF, Heath DD, Al-Delaimy WK, et al. Curcumin content of turmeric and curry powders. Nutrition and Cancer. 2006;55(2):126-131.
  13. Tayyem RF, Heath DD, Al-Delaimy WK, et al. Curcumin content of turmeric and curry powders. Nutrition and Cancer. 2006;55(2):126-131.
  14. Balasubramanian S and Eckert RL. Keratoinocyte proliferation, differentiation, and apoptosis - Differential mechanisms of regulation by curcumin, EGCG and apigenin. Toxicology and Applied Pharmacology. 2007, in press.
  15. Eckert RL, Crish JF, Efimova T, et al. Review. Opposing action of curcumin and green tea polyphenol in human keratinocytes. Mol Nutr Food Res. 2006;50:123-129.