Study of Efficacy of Curcumin in Combination With Chemotherapy in Patients With Advanced Breast Cancer: Randomized, Double Blind, Placebo Controlled Clinical Trial

RATIONALE

Various preclinical, clinical, and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic, as a mediator of chemoresistance, chemopreventive, and as a therapeutic agent. However, the main problem associated with the use of curcumin in humans is its low absorption from the gastrointestinal tract, poor solubility in body fluids and low bioavailability. To overcome the pharmacokinetic and bioavailability limitations of oral administration, water soluble curcumin, Curcumin® (CUC-01) injection, a clear, yellow viscous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion was elaborated. Curcumin® (CUC-01) injection is patented pharmacy product and sold per individual prescription in Germany and other countries for Cancer Centers. However, clinical efficacy and safety of these formulation have to be confirmed in this study.

Development of multidrug resistance (MDR) against a variety of conventional and novel chemotherapeutic agents is a significant challenge in effective cancer therapy. Paclitaxel, one of the most prescribed conventional chemotherapeutic agents, acts as microtubule stabilizer and blocks cancer cells in the G2/M phase, thus preventing them from mitosis. It is also an apoptosis inducer in cancer cells. However, one of the main drawbacks of its use is that it is also a substrate of P-gp and treatment with PCL induces the overexpression of the efflux pump in the cancer cells. NF-κB is a transcription factor that controls the expression of genes involved in a number of physiological responses including differentiation, inflammation, apoptosis and upregulation of the P-gp. The PI3K/Akt pathway is also another over-activated pathway in a wide range of tumor types and therefore its over-activation leads to increased cancer-cell survival, proliferation, and growth and it also promotes NF-κB activity, all affects the success of the chemotherapy with Paclitaxel. Curcumin is known to downregulate both the PI3K/Akt and NF-κB pathways independent of each other, and thus it can act as a mediator of chemoresistance by sensitizing cancer cells to a conventional chemotherapeutic agents.

It has been suggested that co-administration of Paclitaxel and curcumin will help to overcome multidrug resistance in cancer. Synergistic interaction of curcumin and paclitaxel was demonstrated in paclitaxel (Taxol)-resistant breast cancer cells, human breast cancer xenograft model, in MDA-MB-231 and MCF-7 human breast cancer cells and many other cancer cell lines. In vivo, this combination treatment produced a three-fold tumor inhibition with each of these cell lines. Furthermore, the combination of paclitaxel and curcumin exerted increased anti-tumor efficacy on mouse models These results clearly indicate combination of Curcumin with paclitaxel could have significant clinical advantages for the treatment of breast cancer.

Curcumin exerted in vitro anti-breast cancer activities through regulation of matrix metalloproteinase (MMP)-2, B-cell lymphoma 2 (Bcl-2), Bax, flap endonuclease 1 (Fen1), NF-E2-related factor 2 (Nrf-2) factors, and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling.