Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells.
OBJECTIVE
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family that preferentially kills tumor cells. In this study, we sought to determine whether chemotherapeutic agents augment TRAIL-induced cytotoxicity in human prostate cancer cells, and whether this sensitivity can be blocked by overexpression of bcl-2.


METHODS
Prostate cancer cells, PC3 and LNCaP, were treated with TRAIL alone, drug alone or a combination of both for 24 h. Cytotoxicity was determined by DNA fragmentation and clonogenic survival assay.


RESULTS
Treatment with the conventional chemotherapeutic agents cisplatin (2 and 5 microg/ml), etoposide (10 microM and 20 microM) and doxorubicin (30 and 60 n M) dramatically augmented TRAIL-induced apoptosis in LNCaP and PC3 cells. TRAIL-induced apoptosis was partially abrogated by overexpression of bcl-2 in these two cell lines when it was used in combination with the above agents. Similar results were obtained using clonogenic survival assays where bcl-2 overexpression was also found to marginally protect against TRAIL- and chemotherapy-induced cell killing.


CONCLUSIONS
This study demonstrates that combination treatment of prostate cancer cells with TRAIL and chemotherapeutic agents overcomes their resistance by triggering caspase activation. This greater than additive effect of cotreatment with TRAIL and chemotherapy may provide the basis for a new therapeutic approach to induce apoptosis in otherwise resistant cancer cells.
Department of Experimental Radiation Oncology, Box 066, U T M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
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Munshi
T J
TJ
McDonnell
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Meyn
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D004317:Doxorubicin; D020169:Caspases; D002945:Cisplatin