title: X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells.
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.
authors.affiliation: AVI BioPharma, Inc., 4575 SW Research Way, Suite 200, Corvallis, OR 97333, USA.
authors.forename: Adams
authors.initials: A
authors.lastname: Amantana
authors.forename: Carla A
authors.initials: CA
authors.lastname: London
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000819:agonists / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D060172:Morpholinos; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines; D060172:Morpholinos; D020319:Oligodeoxyribonucleotides, Antisense; D011506:Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin