PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells

We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, w...

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Published in:	PloS one Vol. 7; no. 12; p. e52898
Main Authors:	Marklein, Diana, Graab, Ulrike, Naumann, Ivonne, Yan, Tiandong, Ridzewski, Rosalie, Nitzki, Frauke, Rosenberger, Albert, Dittmann, Kai, Wienands, Jürgen, Wojnowski, Leszek, Fulda, Simone, Hahn, Heidi
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 31-12-2012 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase Accumulation Animals Anthracycline Anthracyclines Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Apoptosis - drug effects ATP Binding Cassette Transporter, Sub-Family B ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Bax protein bcl-2-Associated X Protein - metabolism Biology Cancer therapies Caspase Caspase 3 - metabolism Caspase-3 Cell growth Cell Line, Tumor Chemotherapy Cytochromes c - metabolism Doxorubicin Doxorubicin - administration & dosage Drug Resistance, Neoplasm Drug Synergism Drugs Enzyme Activation - drug effects Furans - administration & dosage Gene expression Gene Expression - drug effects Genetics Glioblastoma Humans Immunology Indazoles - administration & dosage Inhibition Inhibitors Kinases Leukemia MDR1 protein Medical research Medicine Mice Mice, Nude Mitochondria Multidrug Resistance-Associated Proteins - drug effects Neuroblastoma Pediatrics Permeability Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Pyridines - administration & dosage Pyrimidines - administration & dosage Sarcoma Sarcoma - drug therapy Sarcoma - enzymology Signal transduction Sulfonamides - administration & dosage TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism Tumor Burden - drug effects Tumor cell lines Tumor cells Tumors Xenograft Model Antitumor Assays Xenografts Germany
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Summary:	We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: DM UG IN TY FN KD LW SF HH. Performed the experiments: DM UG IN TY RR FN. Analyzed the data: DM UG IN TY RR FN KD AR. Contributed reagents/materials/analysis tools: JW LW SF HH. Wrote the paper: DM LW SF HH.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0052898