Protandim ~ Approach for Cancer Prevention

 Protandim Studies

Oxidative stress is an important contributor to cancer development. Consistent with that, antioxidant enzymes have been demonstrated to suppress tumorigenesis when being elevated both in vitro and in vivo, making induction of these enzymes a more potent approach for cancer prevention. Protandim, a well-defined combination of widely studied medicinal plants, has been shown to induce superoxide dismutase (SOD) and catalase activities and reduce superoxide generation and lipid peroxidation in healthy human subjects. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandim-containing basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. 1Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-κB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention.

Citation: Liu J, Gu X, Robbins D, Li G, Shi R, et al. (2009) Protandim, a Fundamentally New Antioxidant Approach in Chemoprevention Using Mouse Two-Stage Skin Carcinogenesis as a Model. PLoS ONE 4(4): e5284. doi:10.1371/journal.pone.0005284
Editor: Joseph Alan Bauer, Cleveland Clinic, United States of America

Received: February 11, 2009; Accepted: March 20, 2009; Published: April 22, 2009
Copyright: © 2009 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The Skin Cancer Foundation. http://www.skincancer.org/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: yzhao1@lsuhsc.edu

Introduction Top

Cancer is affected by alterations in multiple physiological events including apoptosis, inflammation, differentiation, and angiogenesis. Oxidative stress, resulting from the imbalance between antioxidants and prooxidants, has been recognized to play an important role in cancer development. Consistent with that, antioxidant enzymes, especially superoxide dismutase (SOD), have been demonstrated to reduce tumorigenesis both in vitro and in vivo [1]–[2].

SOD not only suppresses cell proliferation, but also affects inflammation. The association between chronic inflammation and cancer is now well established [3]–[7]. One important mechanism of inflammation-induced cancer is due to oxidative stress [8]–[11], which results from the release of free radicals from activated immune cells and cytokines.

A new approach to antioxidant therapy via the induction of antioxidant enzymes (including SOD and catalase) has been developed [12]. The dietary supplement, Protandim, is a combination of five phytochemicals from medicinal plants long recorded in traditional Indian and Chinese medicine. One capsule of Protandim (675 mg) consists of the following: B. monnieri (45% bacosides), 150 mg; S. marianum (70–80% silymarin), 225mg; W. somnifera (1.5% withanolides), 150 mg; C. sinensis (98% polyphenols and 45% (-)-epigallocatechin-3-gallate), 75 mg; and C. longa (95% curcumin), 75 mg [12]. Protandim has been tested in healthy human subjects, producing increased SOD and catalase activities and decreased lipid oxidation levels in the blood samples without causing overt toxicity [12]. Being a critical step, studies have been performed to optimize the dosing of Protandim. At the current dose, none of the five ingredients alone significantly induces antioxidant enzymes; however, subtraction of any ingredient significantly reduces the induction. In summary, the bioactivities of each ingredient form a synergistic effect when combined [13].

In this study, the cancer preventative activity of Protandim is tested using a well-established two-stage skin carcinogenesis mouse model. The mouse skin carcinogenesis is a well-developed model to screen anti-cancer reagents. In this model, a tumor initiator (e.g., dimethylbenz[a]anthracene [DMBA]) is first treated to cause mutations of the oncogene Ras. A tumor promoter (e.g., 12-O-tetradecanoylphorbol-13-acetate [TPA]) is then applied to selectively promote the growth of Ras-mutated skin epidermal cells. As a phorbor ester, TPA can directly activate protein kinase C [14]. However, low concentrations of TPA can also exert inhibitory effect on cell proliferation either alone or in combination with anti-cancer drugs in human pancreas cancer cells [15], and human prostate cancer cells [16], [17]. A phase I dose escalation trial of TPA has been performed in patients with relapsed or refractory malignancies and the tolerated dose has been established [18].