Extensive research over the past 5 decades has suggested the therapeutic potential of curcumin (diferuloylmethane), a polyphenol derived from the plant Curcuma Ionga, in the prevention and treatment of cancer based on its in vitro and in vivo anti-tumor activity in animal models. Curcumin has been shown to inhibit the proliferation of a wide variety of tumor cells, It inhibits angiogenesis, induces apoptosis or cell cycle arrest, and causes regression of tumors in preclinical models. In addition, curcumin has been consumed as a part of the human diet for centuries without significant toxicity. In phase 1 clinical trials it has been well tolerated at doses up to 8 gms/day. However, curcumin has a poor oral bioavailability and optimal biologic dose has not been determined. Multiple myeloma is a clonal malignancy of plasma cells, affecting 13,000 of Americans each year. It is characterized by monoclonal gammopathy, hypercalcemia, renal failure, anemia, and increased susceptibility to infections. Multiple myeloma remains an incurable disease with a median survival of 3 years. Thus, the search continues for a safe and effective treatment. Recent work from our group has shown that NF-kappaB is constitutively active in human myeloma cells and that curcumin down-regulates NF-kappaB in human myeloma cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of this disease with this pharmacologically safe agent. Bioperine is a thermonutrient that has been shown to increase the serum levels of several drugs and other nutrients. Based on these observations, we propose a clinical trial of curcumin alone (at 4 dose levels) or in combination with Bioperine (at a fixed dose) in patients with multiple myeloma. We hypothesize that at the doses proposed, oral consumption of curcumin will be well tolerated, plasma concentrations of curcumin will be elevated when administered concomitantly with Bioperine, will inhibit activation of NFkappaB, and will down regulate NF-kappaB related genes responsible for survival and proliferation of malignant cells.
Our specific aims are therefore to define the safe and biologically active dose(s) of curcumin in disease where it has shown very impressive in vitro activity. In addition, we will evaluate whether addition of Bioperine can increase the bioavailability of curcumin. Finally, we will examine the effect of treatment on NF-kappaB and related genes as evidence for biologic response to treatment. Knowledge gained from these studies may provide useful information on how best to use these natural products in the treatment of cancer.
