Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25285768
DOI
10.1016/j.bcp.2014.09.013
PII: S0006-2952(14)00557-7
Knihovny.cz E-resources
- Keywords
- Apoptosis, Cisplatin, Colon cancer, LA-12, TRAIL,
- MeSH
- Amantadine analogs & derivatives pharmacology MeSH
- Apoptosis drug effects genetics MeSH
- Cisplatin pharmacology MeSH
- Genes, p53 MeSH
- HCT116 Cells drug effects MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Mitochondria drug effects metabolism MeSH
- Tumor Cells, Cultured MeSH
- Colonic Neoplasms drug therapy metabolism pathology MeSH
- Organoplatinum Compounds pharmacology MeSH
- bcl-2 Homologous Antagonist-Killer Protein metabolism MeSH
- TNF-Related Apoptosis-Inducing Ligand metabolism pharmacology MeSH
- bcl-2-Associated X Protein genetics metabolism MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-bcl-2 metabolism MeSH
- Proto-Oncogene Proteins c-myc genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amantadine MeSH
- BAK1 protein, human MeSH Browser
- BAX protein, human MeSH Browser
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
- Cisplatin MeSH
- Organoplatinum Compounds MeSH
- bcl-2 Homologous Antagonist-Killer Protein MeSH
- TNF-Related Apoptosis-Inducing Ligand MeSH
- bcl-2-Associated X Protein MeSH
- Antineoplastic Agents MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- Proto-Oncogene Proteins c-myc MeSH
- TNFSF10 protein, human MeSH Browser
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.
References provided by Crossref.org
Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
