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

Jarmila Lauková; Alois Kozubík; Jiřina Hofmanová; Jana Nekvindová; Petr Sova; Mary Pat Moyer; Jiří Ehrmann; Alena Hyršlová Vaculová

doi:10.1371/journal.pone.0141020

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

PLoS One. 2015 Oct 22;10(10):e0141020. doi: 10.1371/journal.pone.0141020. eCollection 2015.

Authors

Jarmila Lauková¹, Alois Kozubík¹, Jiřina Hofmanová¹, Jana Nekvindová², Petr Sova³, Mary Pat Moyer⁴, Jiří Ehrmann⁵, Alena Hyršlová Vaculová⁶

Affiliations

¹ Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
² Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
³ Platinum Pharmaceuticals, a.s., Brno, Czech Republic.
⁴ INCELL Corporation LLC, San Antonio, Texas, United States of America.
⁵ Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
⁶ Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic.

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amantadine / analogs & derivatives*
Amantadine / pharmacology
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy*
Drug Synergism
Energy Metabolism / drug effects
G1 Phase Cell Cycle Checkpoints / drug effects
HCT116 Cells
Humans
Membrane Potential, Mitochondrial / drug effects
Mitochondria / metabolism
Organoplatinum Compounds / pharmacology*
PPAR gamma / genetics
PTEN Phosphohydrolase / genetics*
RNA Interference
RNA, Small Interfering
Rosiglitazone
Thiazolidinediones / pharmacology*
Tumor Suppressor Protein p53 / genetics

Substances

Antineoplastic Agents
Organoplatinum Compounds
PPAR gamma
RNA, Small Interfering
Thiazolidinediones
Tumor Suppressor Protein p53
bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)
Rosiglitazone
Amantadine
PTEN Phosphohydrolase
Pten protein, mouse

Grants and funding

This work was supported by the Czech Science Foundation (15-06650S)(http://www.gacr.cz; AHV) and IGA of the Ministry of Health of the Czech Republic (NT 11201-5/2010) (http://iga.mzcr.cz; AK). Platinum Pharmaceuticals, a.s. (Dr. Petr Sova) and INCELL Corporation LLC (Dr. Mary Pat Moyer) provided support in the form of research material, and their specific role is also indicated within the Author Contributions section of the online submission form.