Publications [#99277] of Gayathri R Devi

Papers Published

1. A Amantana, CA London, PL Iversen, GR Devi, X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells., Molecular cancer therapeutics, vol. 3 no. 6 (June, 2004), pp. 699-707, ISSN 1535-7163
   (last updated on 2013/05/16)

   Abstract:
   Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (>96 hours) with cisplatin (IC(50) = 27.5 to 35.5 micromol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC(50) = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC(50) from >200 micromol/L with cisplatin alone to 9 to 20 micromol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.

   Keywords:
   Apoptosis • Apoptosis Regulatory Proteins • Caspase 3 • Caspases • Cell Line, Tumor • Cisplatin • Drug Resistance, Neoplasm • Enzyme Activation • Gene Expression Regulation, Neoplastic • HeLa Cells • Humans • Male • Membrane Glycoproteins • Morpholines • Morpholinos • Oligodeoxyribonucleotides, Antisense • Prostatic Neoplasms • Proteins • TNF-Related Apoptosis-Inducing Ligand • Tumor Necrosis Factor-alpha • X-Linked Inhibitor of Apoptosis Protein • agonists • antagonists & inhibitors* • drug effects* • drug therapy* • genetics • metabolism • metabolism* • pathology* • pharmacology