Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25285768
DOI
10.1016/j.bcp.2014.09.013
PII: S0006-2952(14)00557-7
Knihovny.cz E-zdroje
- Klíčová slova
- Apoptosis, Cisplatin, Colon cancer, LA-12, TRAIL,
- MeSH
- amantadin analogy a deriváty farmakologie MeSH
- apoptóza účinky léků genetika MeSH
- cisplatina farmakologie MeSH
- geny p53 MeSH
- HCT116 buňky účinky léků MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mitochondrie účinky léků metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádory tračníku farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny farmakologie MeSH
- protein Bak metabolismus MeSH
- protein TRAIL metabolismus farmakologie MeSH
- protein X asociovaný s bcl-2 genetika metabolismus MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amantadin MeSH
- BAK1 protein, human MeSH Prohlížeč
- BAX protein, human MeSH Prohlížeč
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
- cisplatina MeSH
- organoplatinové sloučeniny MeSH
- protein Bak MeSH
- protein TRAIL MeSH
- protein X asociovaný s bcl-2 MeSH
- protinádorové látky MeSH
- protoonkogenní proteiny c-bcl-2 MeSH
- protoonkogenní proteiny c-myc MeSH
- TNFSF10 protein, human MeSH Prohlížeč
In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action.
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