The roles of autophagic cell death and apoptosis induced by topoisomerase inhibitor irinotecan in colon cancer cells with deleted p53 were investigated during 48 h. We report that irinotecan-dependent cytotoxicity and proapoptotic activity were reduced in the present model while autophagy levels significantly increased. Upon p53 transfection, cell demise rates increased, with cells bearing the features of apoptosis and autophagic cell death. The subsequent studies into mechanisms of cell death process revealed the important role of Bax in mediating mitochondrial and lysosomal leakage which might serve as leading signals for both apoptosis and autophagic cell death. These results suggest that different modes of cell death in p53 null colon cancer cells treated with cytostatics (irinotecan) may be activated simultaneously. Moreover, their interactions possibly occur at several stages and aren't mutually exclusive. This might thus lead to a potential synergism with interesting therapeutic ramifications.

Department of Medical Biology and Genetics Charles University Faculty of Medicine in Hradec Kralove Simkova 870 500 38 Hradec Kralove Czech Republic

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Selected Aspects of Chemoresistance Mechanisms in Colorectal Carcinoma-A Focus on Epithelial-to-Mesenchymal Transition, Autophagy, and Apoptosis