CURCUMIN INCREASES SENSITIVITY OF RESISTANT OVARIAN TUMOUR CELLS TO PLATINUM DRUGS: APOPTOTIC EFFECTS AND CELL-CYCLE ALTERATIONS.

Cisplatin (CDDP) and oxaliplatin are first-line drugs in treatment of many types of epithelial cancer and their combination with other cytostatics are under investigation to limit side effects and resistance to them in clinical therapy of ovarian cancer1. New strategies to improve clinical response and to reduce toxicity of cancer therapy focus on chemoprevention, which hopes to identify substances that can suppress transformation of initiated or precancerous cells to malignant ones 2. To improve the platinum drugs' pharmacological profile, combination with resistance modulators or newly molecularly targeted drugs are under preclinical and clinical investigation. Alteration of appropriate cell-cycle progression and of closely related apoptotic process is a basic feature of tumour cells, and development of new tumour-targeted agents focus on apoptosis, either during cell-cycle arrest or following premature cell-cycle checkpoint exit. Increasingly epidemiological, experimental and clinical trials suggest study the effect of curcumin, the principal curcuminoid of the popular Indian curry spice turmeric, on numerous diseases including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer 3. Curcumin protects against cancer, not only because of its well-known antioxidant properties, but also because it modulates intracellular signalling, which is related to cell proliferation and apoptosis 4. OBJECTIVES: The aim of this study was to evaluate the efficacy of a combined treatment using curcumin with cisplatin or with oxaliplatin in a human ovarian cancer cell line (2008) and in its cisplatin-resistant variant (C13) mainly on cell viability, and cell cycling and apoptosis measured by flow cytometry. RESULTS: Curcumin per se caused significant concentration-dependent (0.1-100 \uf06dM) and time-persistent (24-72 h) reduction of cell proliferation, altered cell-cycle phases and induced apoptosis, as well as it caused ROS generation and altered intracellular glutathione content both in wild type and in CDDP-resistant cancer cell lines. When carcinoma cells were simultaneously exposed to curcumin and to CDDP or to oxaliplatin (at concentrations lower than IC50) cancer cell viability was reduced more than with single-drug treatment. Moreover, dose and time related effects of curcumin, when combined with platinum drugs, were linked to consistent reduction in cell cycling and increased apoptosis, in comparison with single-drug treatment. These effects were significant both in wild type and in CDDP-resistant cells, indicating that curcumin was also able to increase the sensitivity of resistant ovarian cancer cells to cisplatin. CONCLUSIONS: The data suggests that curcumin is a natural compound of potential interest in combination with platinum drugs possibly limiting side effects and resistance and increasing the clinical impact of chemotherapy in ovarian cancer patients. 1. H\uf6gberg T, Glimelius B, Nygren P (2001). A systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol.;40(2-3):340-60. 2. Howells LM, Manson MM (2005) Prospects for plant-derived chemopreventive agents exhibiting multiple mechanisms of action. Curr. Med. Chem. Anticancer Agents 5, 201\u2013213. 3. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008). "Curcumin: from ancient medicine to current clinical trials". Cell. Mol. Life Sci. 65 (11): 1631\u201352. 4. Montopoli M, Ragazzi E, Froldi G, Caparrotta L. (2009) Cell cycle inhibition and apoptosis induced by curcumin combined with cisplatin or oxaliplatin in human ovarian carcinoma cell lines. Cell Proliferation 42(2):195-206