Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.

Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Cytokinetics Institute of Biophysics Czech Academy of Sciences v v i Brno Czech Republic

Department of Cytokinetics Institute of Biophysics Czech Academy of Sciences v v i Brno Czech Republic Center of Biomolecular and Cellular Engineering International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Department of Cytokinetics Institute of Biophysics Czech Academy of Sciences v v i Brno Czech Republic Department of Animal Physiology and Immunology Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Urology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Institute of Biotechnology Czech Academy of Sciences v v i Praha Czech Republic

Platinum Pharmaceuticals a s Brno Czech Republic

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$a Vondálová Blanářová, Olga $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic.

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$a Cisplatin or LA-12 enhance killing effects of TRAIL in prostate cancer cells through Bid-dependent stimulation of mitochondrial apoptotic pathway but not caspase-10 / $c O. Vondálová Blanářová, B. Šafaříková, J. Herůdková, M. Krkoška, S. Tománková, Z. Kahounová, L. Anděra, J. Bouchal, G. Kharaishvili, M. Král, P. Sova, A. Kozubík, A. Hyršlová Vaculová,

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$a Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.

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$a Šafaříková, Barbora $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.

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$a Herůdková, Jarmila $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.

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$a Krkoška, Martin $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.

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$a Tománková, Silvie $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic.

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$a Kahounová, Zuzana $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic. Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.

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$a Anděra, Ladislav $u Institute of Biotechnology, Czech Academy of Sciences, v.v.i., Praha, Czech Republic.

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$a Kozubík, Alois $u Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.

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