Abstract
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.
MeSH terms
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Amantadine / analogs & derivatives*
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Amantadine / pharmacology
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Apoptosis / drug effects*
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BH3 Interacting Domain Death Agonist Protein / metabolism*
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Caspase 10 / metabolism*
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Cisplatin / pharmacology*
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Humans
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Male
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Organoplatinum Compounds / pharmacology*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
Substances
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Organoplatinum Compounds
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TNF-Related Apoptosis-Inducing Ligand
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bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)
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Amantadine
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Caspase 10
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Cisplatin
Grants and funding
This work was supported by the Czech Science Foundation (15-06650S) (
http://www.gacr.cz, AHV), Czech Ministry of Health (NV15-28628A) (
www.mzcr.cz, JB), grant HistoPARK (CZ.1.07/2.3.00/ 20.0185), project no. LQ1605 from the National Program of Sustainability II (MEYS CR) (
http://www.msmt.cz), by the European Union – project ICRC-ERAHumanBridge (No. 316345) (
http://www.icrc-era-humanbridge.eu), and by Brno City Municipality (Brno Ph.D. Talent, MK) (
http://www.jcmm.cz/en/phd-students.html). These funders provided support in the form of salaries for authors [OVB, JH, MK, ZK, JB, GK, MK, AK, AHV], but had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Platinum Pharmaceuticals provided support in the form of the LA-12 supply and information about physicochemical properties of the compound, in the form of salaries for one of the co-authors [PS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.