Antagonism between curcumin and the topoisomerase II inhibitor etoposide: a study of DNA damage, cell cycle regulation and death pathways.
The use of combinations of chemotherapy and natural products has recently emerged as a new method of cancer therapy, relying on the capacity of certain natural compounds to trigger cell death with low doses of chemotherapeutic agents and few side effects. The current study aims to evaluate the modulatory effects of curcumin (CUR), Nigella sativa (NS) and taurine on etoposide (ETP) cytotoxicity in a panel of cancer cell lines and to identify their underlying mechanisms.   CUR alone showed potent antitumor activity, but surprisingly, its interaction with ETP was antagonistic in four out of five cancer cell lines. Neither taurine nor Nigella sativa affect the sensitivity of cancer cells to ETP. Examination of the DNA damage response machinery (DDR) showed that both ETP and CUR elicited DNA double-strand breaks (DSB) and evoked γ-H2AX foci formation at doses as low as 1 µg/ml. Cell cycle analysis revealed S phase arrest after ETP or CUR application, whereas co-treatment with ETP and CUR led to increased arrest of the cell cycle in S phase (MCF-7 cells) or the accumulation of cells in G 2/M phases (HCT116, and HeLa cells). Furthermore, cotreatment with ETP and CUR resulted in modulation of the level of DNA damage induction and repair compared with either agent alone. Electron microscopic examination demonstrated that different modalities of cell death occurred with each treatment. CUR alone induced autophagy, apoptosis and necrosis, whereas ETP alone or in combination with CUR led to apoptosis and necrosis.


CONCLUSIONS
Cotreatment with ETP and CUR resulted in an antagonistic interaction. This antagonism is related, in part, to the enhanced arrest of tumor cells in both S and G 2/M phases, which prevents the cells from entering M-phase with damaged DNA and, consequently, prevents cell death from occurring. This arrest allows time for the cells to repair DNA damage so that cell cycle -arrested cells can eventually resume cell cycle progression and continue their physiological program.
Clinical Biochemistry and Molecular Biology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt. ekramsaleh@hotmail.com
Ekram M
EM
Saleh
Raafat A
RA
El-awady
Nadia A
NA
Eissa
Wael M
WM
Abdel-Rahman
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004249:DNA Damage; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D013654:Taurine / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D059005:Topoisomerase II Inhibitors; D013654:Taurine; D005047:Etoposide; D003474:Curcumin