Dataset Information

Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells.

ABSTRACT: 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 PPAR? 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.

SUBMITTER: Laukova J

PROVIDER: S-EPMC4619604 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells.

Lauková Jarmila J Kozubík Alois A Hofmanová Jiřina J Nekvindová Jana J Sova Petr P Moyer Mary Pat MP Ehrmann Jiří J Hyršlová Vaculová Alena A

PloS one 20151022 10

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 de ...[more]

PMID: 26492315

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Project description:The selection of drug candidates for entering clinical development relies on in vivo testing in (solid) tumor animal models. However, the heterogeneity of tumor tissue (e.g. in terms of drug uptake or tissue composition) is rarely considered when testing novel drug candidates. Therefore, we used the murine colon cancer CT-26 tumor model to study the spatially-resolved drug distribution in tumor tissue upon repetitive treatment of animals over two weeks with three investigational platinum(IV)-based anticancer agents, oxaliplatin or satraplatin. A quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method revealed a heterogeneous platinum distribution, which correlated well with the histologic features of the tumor and surrounding tissue at the microscopic level. In most of the cases, higher amounts of intratumoral platinum were found in the surrounding tissue than in the malignant parts of the sample. This indicates that determination of average platinum amounts (e.g. by microwave-assisted digestion of the sample followed by analysis with ICP-MS) might overestimate the drug uptake in tumor tissue causing misleading conclusions. In addition, we studied the platinum distribution in the kidneys of treated animals to probe if accumulation in the cortex and medulla predict potential nephrotoxicity. A 10-fold increase of platinum in the cortex of the kidney over the medulla was observed for oxaliplatin and satraplatin. Although these findings are similar to those in the platinum distribution of the nephrotoxic anticancer drug cisplatin, treatment with the compounds of our study did not show signs of nephrotoxicity in clinical use or clinical trials (oxaliplatin, satraplatin) and did not result in the alteration of renal structures. Thus, predicting the side effects based on bioimaging data by LA-ICP-MS should be considered with caution. To the best of our knowledge, this is the first LA-ICP-MS study on spatially-resolved platinum accumulation in tissues after repetitive platinum-based anticancer drug treatment of mice bearing a preclinical tumor model.

Dataset Information

Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells.

Publications

Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells.

Similar Datasets

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