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
• Amantadine analogs & derivatives   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cisplatin pharmacology   MeSH
• Caspase 10 metabolism   MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Prostatic Neoplasms metabolism   pathology   MeSH
• Organoplatinum Compounds pharmacology   MeSH
• BH3 Interacting Domain Death Agonist Protein metabolism   MeSH
• TNF-Related Apoptosis-Inducing Ligand metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amantadine MeSH
• BID protein, human MeSH Browser
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
• Cisplatin MeSH
• Caspase 10 MeSH
• Organoplatinum Compounds MeSH
• BH3 Interacting Domain Death Agonist Protein MeSH
• TNF-Related Apoptosis-Inducing Ligand MeSH

Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.

• MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   genetics   MeSH
• Checkpoint Kinase 1 antagonists & inhibitors   genetics   metabolism   MeSH
• Cisplatin pharmacology   MeSH
• Gene Knockout Techniques MeSH
• Cyclin-Dependent Kinase Inhibitor p21 genetics   metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Colonic Neoplasms drug therapy   genetics   metabolism   pathology   MeSH
• DNA Damage drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Pyrazoles pharmacology   MeSH
• Pyrimidines pharmacology   MeSH
• Platinum Compounds pharmacology   MeSH
• Cellular Senescence drug effects   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Checkpoint Kinase 1 MeSH
• CHEK1 protein, human MeSH Browser
• Cisplatin MeSH
• Cyclin-Dependent Kinase Inhibitor p21 MeSH
• MK-8776 MeSH Browser
• Tumor Suppressor Protein p53 MeSH
• Antineoplastic Agents MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH
• Platinum Compounds MeSH

We demonstrated for the first time an outstanding ability of rosiglitazone to mediate a profound enhancement of LA-12-induced apoptosis associated with activation of mitochondrial pathway in human colon cancer cells. This effect was preferentially observed in the G1 cell cycle phase, independent on p53 and PPARγ proteins, and accompanied with significant changes of selected Bcl-2 family protein levels. Further stimulation of cooperative synergic cytotoxic action of rosiglitazone and LA-12 was demonstrated in the cells deficient for PTEN, where mitochondrial apoptotic pathway was more stimulated and G1-phase-associated dying was reinforced. Our results suggest that combined treatment with rosiglitazone and LA-12 might be promising anticancer strategy in colon-derived tumours regardless of their p53 status, and also favourable in those defective in PTEN function.

• MeSH
• Amantadine analogs & derivatives   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Energy Metabolism drug effects   MeSH
• PTEN Phosphohydrolase genetics   MeSH
• HCT116 Cells MeSH
• G1 Phase Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• RNA, Small Interfering MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Colonic Neoplasms drug therapy   MeSH
• Organoplatinum Compounds pharmacology   MeSH
• PPAR gamma genetics   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• RNA Interference MeSH
• Rosiglitazone MeSH
• Drug Synergism MeSH
• Thiazolidinediones pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amantadine MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
• PTEN Phosphohydrolase MeSH
• RNA, Small Interfering MeSH
• Tumor Suppressor Protein p53 MeSH
• Organoplatinum Compounds MeSH
• PPAR gamma MeSH
• Antineoplastic Agents MeSH
• Pten protein, mouse MeSH Browser
• Rosiglitazone MeSH
• Thiazolidinediones MeSH