The Role of Autophagic Cell Death and Apoptosis in Irinotecan-treated p53 Null Colon Cancer Cells

Stanislav      John; Jan      Mls; Miroslav      Cervinka; Emil      Rudolf

Abstract

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.

Keywords: Irinotecan, Colon cancer, Autophagy, p53, Chemotherapy, Autophagic cell death, Apoptosis, Bax, Lysosomes, Mitochondria.