Targeting XIAP for Chemosensitization Purposes: Different Effect with Different Cytotoxic Drugs.

摘要: Defects in apoptosis have been implicated the resistance of cancer cells to a wide variety anticancer drugs. XIAP, an inhibitor both intrinsic and extrinsic apoptotic pathways by inhibiting caspases-3, -7 -9, has proposed as good molecular target for enhancing effects cytotoxic drugs since: it is widely expressed human cell lines tissues; downregulation XIAP expression enhanced chemotherapeutic agents various line models; correlates with prognosis some cancers, including acute myeloid leukemia. Small molecules able inhibit developed. Furthermore, antisense oligonucleotide inhibitors (AEG35156) are already clinical trials. However, potential chemosensitization effect not thoroughly explored, concerning different tumor models The purpose current study was investigate if enhances doxorubicin cytarabine, used treatment leukemias, vitro model blastic phase Chronic Myeloid Leukemia, K562 line. approach downregulate using: transient transfection siRNAs stable shRNAs cloned into appropriate vector. Two targeting were tested, using two conditions siRNA delivery. Relatively modest observed Western Blot, more potent sequence chosen studies. Our results show that expression: reduced cellular viability but this significant; sensitized (IC50 decreased from 78nM 55nM) cytarabine. To confirm these results, established Modest achieved when compared control shRNA In confirmed sensitizes 68nM 50nM) Further analysis following allowed induced programmed death (with cleavage pro-caspase 3) further reduction protein levels, which probably due process itself. did provide better studying than siRNAs. This fact, together levels downregulation, reflects corresponds previously used. conclusion, may be partially level obtained also mechanisms action drugs, indicating should taken account considering achieving sensitization