Curcumin and the Big 'C'

The Big ‘C’ Summer is almost here, and with it days of sunbathing and feasting on soul foods at that 4th of July throw-down. Sounds wonderful, and we cannot wait to ban our winter blues for good. However, long days of sun exposure add up, and darn if in our excitement we forgot to pick up sunscreen. Can a little sun really do a great deal of damage? We need our Vitamin D, after all!

Unfortunately, we do need to be concerned with the amount of time we spend basking in sun rays. Cutaneous squamous cell carcinoma (SCCa), one of the most common types of human malignancies, is on the rise . With an incidence rate of 1-2million cases annually that has steadily increased over the past few decades, SCCa poses hurdles to not only human health, but also to the cost of public health. Cutaneous squamous cell carcinoma, a form of nonmelanoma skin cancer, is associated with enhanced risk of metastasis as compared with other types of malignancies, in other words the spreading and healthy tissue infiltration of cancer cells from the primary tumor site. Seventy percent (70%) of SCCa cases occur in head and neck , complicating surgical removal. The risk of metastasis and recurrence labbench/histopathology.jpg" width=“300” height=“220” class=“mt-image-right” style=“float: right; margin: 0 0 20px 20px;” /> of physically removed lesions leads to the necessity of multiple surgical interventions, raising concerns of disfigurement and high cost. Along with increasing morbidity and mortality rates, especially in the elderly, high incidence and recurrence of SCCa and the resultant need for series of removal procedures have made squamous cell carcinoma one of most costly cancers in the United States (Chen JG et al).

Risk factors for the development of cutaneous squamous cell carcinoma include chronic UV radiation exposure, i.e. day after long day spent in the sun or frequent trips to tanning beds, and genetic predisposition. Other factors include chronic inflammatory skin lesions . Despite the bad news, especially for us sun-lovers, treatments for cutaneous squamous cell carcinoma do exist, typically consisting of topical drug treatments or surgery. Cryotherapy or ‘freezing off’ lesions, skin cream treatments, and repeated steps of scraping away layers of cancerous cells from a lesion (curettage) followed by sealing off blood vessels with electrical current (electrodessication), are all clinically employed methods of treating SCCa. Topical cream drugs also show promise for small and superficial lesions, where five different cream formulations have gained FDA-approval (Gravitz L). The most notable of these topical creams is a drug named Imiquimod, which enhances the immune response against (pre)malignant cells and promotes apoptosis, a form of diseased cell ‘suicide’. However, surgical excision remains the most ‘widely performed and effective treatment used in practice’ (Minton T).

Better to Prevent Cancer, than to Treat Cancer

Although surgical excision is generally accepted as the most effective clinical treatment, it is hardly ideal. Challenges with local excision of multiple lesions or large areas of ‘condemned skin’, i.e. skin at increased risk for malignancy due to years of damage from prolonged exposure to the deleterious effects of sunbathing or to the carcinogens in cigarette smoke (Cheryl Clark, PhD), have prompted a shift in focus toward chemoprevention of cutaneous malignancies . Chemoprevention is defined as oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer (Wright et al). Chemopreventive agents can be contrasted to chemotherapeutic agents, the latter of which are given at toxic doses to induce apoptosis, the programmed death or ‘suicide’ of malignant or pre-malignant cells. Chemopreventive drugs on the other hand are nontoxic to cells, and often possess anti-inflammatory and antioxidant properties (Clark et al). The goal of chemoprevention, a concept first introduced 35 years ago (Gravitz L), is to “kill off any mutant cells that the immune system misses and do so before they have a chance to become cancerous”. Such drugs need to be inherently benign in order to justify long-term prescription to at-risk but presently healthy individuals.

The NCI’s (National Cancer Institute) Division of Cancer Prevention began an initiative in 1998 ‘to further define and guide research in the field of chemopreventive agents’ 1. The NCI has since sponsored a large series of clinical trials with the aim of exploring and developing chemopreventive agents against a variety of common malignancies , including SCCa. The goal of this initiative in the context of skin cancer is the development of pharmaceuticals or neutraceuticals (food products with medical benefits) that inhibit the formation and progression of cutaneous malignancies following exposure to UV radiation (Phillips et al, Wright et al). Proven chemopreventive agents include Vitamin A and the retinoids, derivatives of Vitamin A. Although proven effective, these agents are associated with adverse side effects, which limit the agents’ applicability in long-term preventative therapies for otherwise healthy individuals.

…the American population has gained a huge interest in neutraceuticals. Those investigated for their value in chemoprevention include βeta-carotenes as found in carrots and pumpkin, lycopene as found in tomatoes, genisteim as an isoflavone compound found in soybeans, selenium as found in nuts and cereals, myricetin as a flavanol found in many types of berries, and ginger. However, we know that too much of a good thing can be a bad thing … so we need to carefully evaluate any “natural” substance as if it were a pharmaceutical to determine the dose that is both effective AND safe for human use. Chemotherapeutic drugs are meant to be high dose for high killing, which unfortunately also comes with unpleasant side effects. A chemopreventive agent should be inexpensive (since the patient will presumably be taking it long term), should be uncomplicated, and hopefully affect a biomarker so you can track the performance of the agent you are taking since there is no tumor to observe “shrinking” as you would with a chemotherapy of an established tumor. – Cheryl Clark, PhD, LSUHSC-Shreveport Otolaryngology/Head and Neck Surgery

Curcumin to Prevent Cutaneous Squamous Cell Carcinoma

A research and surgery team at Louisiana State University in Shreveport has been investigating curcumin as a neutraceutical with chemopreventive properties against squamous cell carcinoma. Curcumin is a naturally occurring polyphenolic compound, a subclass of plant-derived substances (i.e. phytochemicals) that typically demonstrate antioxidant and other beneficial biological properties. Curcumin is the active ingredient in turmeric, an orange-yellow spice that is characteristic of Indian and Thai cuisine as a key ingredient in curry dishes . Curcumin’s historic medicinal value as an anti-inflammatory and antioxidant compound has led to studies of this polyphenol as an anticarcinogenic agent in the inhibition of pancreatic, colon, liver, and oral cavity cancers (Pari et al). Curcumin also has applications in the treatment of skin diseases such as cancer and psoriasis, and in chronic wound healing with antioxidant protection. However, the exact mechanisms of curcumin’s biological activity have generally been obscure. Dr. Cherie Ann O Nathan and her coworkers in Louisiana are helping to elucidate these mechanisms and to pave the way for use of new curcumin-based neutraceuticals as chemopreventive agents for head and neck cancers.

“Given the increasing incidence of skin cancer and even higher incidence of condemned skin in the aging population, the application of curcumin in prevention of skin carcinogenesis holds great potential,” says Dr. Cherie Ann Nathan, Vice-Chairman of Otolaryngology – Head and Neck Surgery at LSU Health Shreveport, and Director of Head and Neck Surgery & Research at the Feist-Weiller Cancer Center. Dr. Nathan is not just a behind-the-lines surgeon 2. She is committed to “improving survival in her head and neck patients through early detection and research”, and she and her group are helping to pioneer the use of curcumin as a safe and natural chemopreventive agent against cutaneous squamous cell carcinoma (SCCa) and other head and neck SCCs in at-risk individuals.

In a study published online in March this year, Jeffrey Phillips and coworkers in Dr. Nathan’s group, along with collaborator Dr. John Clifford, showed, for the first time, curcumin’s ability to inhibit human cutaneous squamous cell carcinomas implanted in immune deficient mice (i.e. in vivo). Despite concerns over poor bioavailability in humans, i.e. poor absorption in the gut and rapid metabolism & elimination from the body , Dr. Nathan’s group demonstrated that curcumin inhibits squamous cell carcinoma tumor growth when supplanted in the diet of tumor-bearing mice. Additionally, the study showed that mice pretreated with daily oral curcumin displayed significant difference in tumor growth as compared to control tumor-bearing mice, even at very early time points after implantation of human cancer grafts. Previous studies by Dr. Nathan’s group bolster the finding that curcumin works more effectively in the pretreatment model versus in the ‘already established tumor’ model, where the latter case may require higher doses of the neutraceutical for effective inhibition of tumor growth (Clark et al). These findings suggest an exciting chemopreventive ‘window of opportunity’ for the use of curcumin to prevent skin carcinogenesis and perhaps prevent the recurrence of tumors from excised regions, provided that the polyphenolic compound be administered prior to the development of significant malignancy or metastasis.

In the study by Phillips et al, severe combined immunodeficient (SCID) mice treated with human skin SCC cell lines were tube fed daily diets of 0, 5, or 15-mg of curcumin paste for approximately one month (24 days) until tumors were harvested and stained with dyes to confirm presence of carcinogenesis and malignant cellular proliferation. Tumors were measured daily, and mice where monitored for signs of distress, such as significant weight loss. The results of the study included significant difference in tumor growth rate seen between control mice and mice treated with 15mg of curcumin, where tumor volume increased 2.3x faster in the control group. No toxicity for was observed even at high daily doses of curcumin, where surviving mice at day 24 had not suffered weight loss or other marked signs of distress. Curcumin-treated mice also displayed dose-dependent decreases in cellular proliferation (decreased production of new cancer cells) as compared with control mice.

Dr. Nathan and coworkers were also able to elucidate the mechanism of curcumin in inhibiting SCC carcinogenesis. Curcumin was found to mediate components of the AKT/mTOR pathway, an intracellular signaling pathway whose persistent activation is characteristic of head and neck cancer . Over-activity of the AKT/mTOR pathway leads to reduced apoptosis (an induced suicide of damaged cells) and thus increased cellular proliferation (Phillips et al), a hallmark of cancer. AKT, a protein kinase, activates mTOR (Mammalian Target Of Rapamycin) 3 , which in turn regulates cell survival, proliferation, growth, and motility, as well as angiogenesis, the growth of new blood vessels that feed tumors and promote metastasis (Beevers et al). The activity of mTOR is mediated through its control over the phosphorylation of (addition of a phosphate PO4 group to) several other proteins and transcription factors, including a specific ribosomal protein called S6. When S6 is activated, i.e. phosphorylated, it is involved in increased cell proliferation. The study by Dr. Nathan’s group found that curcumin is an inhibitor of S6 phosphorylation. Phosphorylated S6 expression was shown to have significantly decreased in human cell line tumors harvested from mice that were fed daily diets of 15mg of curcumin. This result confirms the regulatory effect of curcumin on the AKT/mTOR pathway involved in skin carcinogenesis.

While other neutraceuticals have been investigated as chemopreventive agents against skin cancer, including flavonoids such as certain compounds found in soy beans and pomegranate, limited data exist on the efficacy of these agents as topical creams . Other polyphenols as found in green tea and grape seed extracts, dietary polyphenols that inhibit carcinogenesis via combined antioxidant activity and inhibition of transcription factors in cellular signaling, show promise in mouse studies. However, no successful human trails have been performed with these compounds. On the other hand, curcumin has now been successfully demonstrated as a ‘window of opportunity’ chemopreventive agent for human cutaneous squamous cell carcinoma, a skin cancer often caused by chronic sun exposure. Curcumin has similarly been demonstrated, again by Dr. Nathan’s group, as an inhibitor of adverse effects of nicotine in head and neck cancers, where curcumin blocks nicotine-induced activation of the MTOR pathway, thus blocking cell proliferation and motility (Clark et al). Not only did curcumin inhibit cellular proliferation, but the compound also inhibited migration of head and neck squamous cell carcinoma cell lines, indicating its potential ‘to prevent enhanced tumor invasion and metastasis in vivo’ (Clark et al).

While systemic administration of curcumin has been shown effective, local administration may be even better in many cases, for example in the treatment of tongue carcinomas . Future improvements of curcumin formulations, including potential local controlled-release curcumin nanoparticles (Bisht et al), promise even more pronounced anticarcinogenic effects for this neutraceutical. For now it might be safe to say, put down the cigarette, apply the sunscreen, and Eat up your Chicken Curry!

References:

1. Alam M Ratner. Cutaneous squamous-cell carcinoma. N Engl J Med 344:975-983 (2001)
2. Arora A., Attwood J. Common skin cancers and their precursors. Surg Clin North Am 89: 703-712 (2009)
3. Beevers et al. Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int. J. Cancer: 119, 757-764 (2006)
4. Bisht et al. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. Journal of Nanobiotechnology 5:3 (2007)
5. Chen JG et al. Cost of nonmelanoma skin cancer treatment in US. Dermatol Surg 27: 1035-1038 (2001)
6. Dr. Cherie Ann O Nathan, Head and Neck Cancer Alliance Biography
7. Lauren Gravitz. First Line of Defense. Nature 471: S5-S7 (2011)
8. Minton T. Contemporary Mohs surgery applications. Curr Opin Otolaryngol Head Neck Surg 16:376-380 (2008)
9. Pari et al. Role of curcumin in heath and disease. Arch Physiol Biochem 114: 127-149 (2008)
10. Phillips et al. Curcumin Inhibits Skin Squamous Cell Carcinoma Tumor Growth In Vivo. Otolaryngology – Head and Neck Surgery, Published online March 1, 2011
11. Shehzad et al. Curcumin therapeutic promises and bioavailability in colorectal cancer. Drugs today 46:523-532 (2010)
12. Wright T, Spencer J, Flowers F. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol 54: 933-946 (2006)

Phillips JM, Clark C, Herman-Ferdinandez L, Moore-Medlin T, Rong X, Gill JR, Clifford JL, Abreo F, & Nathan CA (2011). Curcumin Inhibits Skin Squamous Cell Carcinoma Tumor Growth In Vivo. Otolaryngology—head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery PMID: 21493306
Gravitz L (2011). Chemoprevention: First line of defence. Nature, 471 (7339) PMID: 21430719

Tweet Nominate a blog post for The Open Laboratory: The Best Writing on Science Blogs 2011! Footnotes 1. National Cancer Institute Preventing Cancer post at StayWellSolutions 2. Since 1996, Dr. Nathan has been actively involved in the free screenings and education for head and neck cancer. Thanks to Feist-Weiller Cancer Center’s Partners in Wellness mobile screening unit, Dr. Nathan’s program has extended free screenings from the clinic to regional hospitals and colleges, a homeless shelter, Barksdale Air Force Base and a 5K run. Dr. Nathan is committed to improving survival in her head and neck patients through early detection and research. – Head and Neck Cancer Alliance Biography 3. Rapamycin – an immunosuppressant drug