April 30, 2015
The evidence is growing that curcumin, the substance in tumeric, should take a bigger role in the human diet for its ability to act as an antioxidant, anti-inflammatory and lipid lowering agent. Western Australian researcher, Gautam Sethi, from Curtin University (Australia), and his colleagues see strong potential, based on this scientific review of past clinical trials, for curcumin and cancer. To date the studies are small in scope, but Sethi and his team see evidence for larger studies. Published in Molecules, Vol. 20, No. 2, Feb 2015.
ABSTRACT: Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years, according to a new research review in curcumin. The researchers cite that available anti-cancer drugs exhibit limited efficacy, are associated with severe side effects, and they are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects.
Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers.
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Curtin University adjunct research fellow Gautam Sethi says most diseases, including cancer, are caused by the deregulation of multiple genes. “To treat cancer you need multi-targeted agents, better than mono-targeted agents, which have been used for the past few years,” Associate Professor Sethi says. “Multi-targeted agents are those that target more than one deregulated oncogenic signaling cascades—they are more effective in treating cancer as it has been found that several genes are mutated in a given cancer. “We can modulate several of such oncogenic genes, which are deregulated in cancer using curcumin.”
A/Prof Sethi says curcumin is exceptionally effective for multiple myeloma patients and those suffering from the particularly lethal pancreatic cancer, for which there are no drugs. However, curcumin was not found to be as effective in breast cancer patients being treated with the chemotherapeutic agent cyclophosphamide. According to the research, curcumin can counteract the effect of cyclophosphamide.
Curcumin safe in high doses
A/Prof Sethi says curcumin is possibly the only drug that can be given at high doses—up to 12g—without any toxicity. “It can target most of the oncogenic proteins like NF-kB, STAT3, AP-1,” he says.
A/Prof Sethi says the only known side effect of the agent is blood thinning, and therefore advises against taking curcumin if undergoing surgery. A/Prof Sethi says it would be ideal to combine curcumin with other drugs or natural compounds, like piperine, an alkaloid found in pepper to increase its bioavailabilty.
“If we combine it with piperine we see viability increase by 2000 per cent 45 minutes after administering the curcumin,” he says. A/Prof Sethi says there is a lack of data to explain the underlying mechanism of its effect, however, it is known for its anti-inflammatory effects. “It has been shown that most chronic diseases, including cancer, are caused by inflammation and can be treated by anti-inflammatory agents.”
He says more work needs to be done to improve curcumin’s viability, as body tissues quickly absorb it.
Study Excerpts for Multiple Myeloma and Pancreatic Cancer
(link at the bottom of this article for the full study and references)Multiple Myeloma
The chemopreventive potential of curcumin in monoclonal gammopathy of undetermined significance (MGUS), a high-risk condition for progression to multiple myeloma, was tested by Golombick et al., in a cross-over study design . Out of 27 patients, 17 received 4000 mg of curcumin for 3 months before cross-over to placebo. The rest received placebo first, followed by curcumin. The levels of paraprotein and urinary N-telopeptide from type I collagen decreased in some patients. The same group reported beneficial effects of curcumin in MGUS in another randomized, double blind, placebo-controlled cross-over study . A phase I/II trial by Vadhan-Raj et al., in 29 patients with asymptomatic, relapsed, or plateau phase multiple myeloma showed a decrease in expression of NF-κB, COX-2, and STAT3 in peripheral blood mononuclear cells and stable maintenance of disease . The patients were given either oral dose of curcumin alone (2000, 4000, 6000, 8000, or 12,000 mg/day) or in combination with 10 mg of bioperine. 12 patients continued the treatment for 12 weeks, followed by combination treatment for five patients (one at a dose of 4000, two at 6000 mg, and two at 8000 mg) for 1 year. Further, well-controlled clinical trials with larger sample sizes are required to substantiate the efficacy of curcumin against multiple myeloma.Pancreatic Cancer
Dhillon et al., conducted a phase II clinical trial in 25 advanced pancreatic cancer patients . An oral dose of 8000 mg of curcumin was given every day until disease progression, with restaging performed every 2 months. Low, steady-state levels of curcumin and its conjugates were detected in the peripheral circulation for the first 4 weeks with a peak at 22–42 ng/mL. In two patients, a biological effect was seen and in one the disease was maintained stably for 18 months. Remarkably, a significant but brief tumor regression was seen in one patient with a concomitant increase in serum cytokine levels. NF-κB, COX-2, and STAT3 suppression in peripheral mononuclear cells was also observed in the patients. Although oral curcumin was found to be safe and well-tolerated, poor bioavailability still remains an issue, which partly explains the biologic activity observed only in some patients. In another open-label, phase II trial, a combination of curcumin and gemcitabine was tested in advanced pancreatic cancer patients . Seventeen patients were administered 8000 mg of curcumin orally every day for 4 weeks while 1000 mg/m3 of gemcitabine were given intravenously three times a week. In five patients, curcumin or the whole treatment was discontinued due to toxicity and one patient died suddenly. In the remaining 11 patients, a partial response was seen; four had stable disease while in six the tumor progressed. Tumor progression time was 1–12 months, with overall survival time of 1–24 months, indicating a modest efficacy of the combination therapy. Also, the authors concluded that 8000 mg/day of curcumin with gemcitabine was above the maximum tolerated dose. In a recent phase I/II trial by Kanai et al., a similar combination of gemcitabine and curcumin was used to treat gemcitabine-resistant pancreatic cancer in 21 patients . In contrast, the combination of gemcitabine and curcumin 8000 mg/day was found to be safe and well tolerated in this study. Studies in a larger cohort are required to validate the results.
A plethora of in vitro and in vivo research together with clinical trials conducted over the past few decades substantiate the potential of curcumin as an anti-cancer agent. At the molecular level, curcumin targets numerous pathways, highlighting its ability to inhibit carcinogenesis at multiple levels and thus, potentially circumventing the development of resistance. However, there is a paucity of data to explain the underlying mechanism of its activity. Clinical trials with curcumin indicate safety, tolerability, non-toxicity (even up to doses of 8000 mg/day), and efficacy. These studies provide a solid foundation for more well-controlled studies in larger cohorts as well as open avenues for future drug development. However, curcumin activity is limited by its poor bioavailability and some possible adverse effects. The development of formulations of curcumin in the form of nanoparticles, liposomes, micelles or phospholipid complexes to enhance its bioavailability and efficacy are still in its early stages. Nonetheless, curcumin has established itself as a safe and promising molecule for the prevention and therapy of not only cancer but also other inflammation-driven diseases.