Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1

• Published in: PloS one Vol. 8; no. 1; p. e55509
• Main Authors: Sims, Jonathan T, Ganguly, Sourik S, Bennett, Holly, Friend, J Woodrow, Tepe, Jessica, Plattner, Rina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2013; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Anthracycline; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Benzamides - pharmacology; Biology; Breast cancer; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Chemoresistance; Chemotherapy; Deoxyribonucleic acid; DNA; Doxorubicin; Doxorubicin - pharmacology; Drug dosages; Drug Resistance, Neoplasm - genetics; Drugs; Efflux; G2 Phase Cell Cycle Checkpoints - drug effects; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma cells; HSP27 Heat-Shock Proteins - metabolism; Hsp27 protein; Humans; Imatinib; Imatinib Mesylate; Insulin; Kinases; Localization; M Phase Cell Cycle Checkpoints - drug effects; Medicine; Melanoma; Metastases; Metastasis; Models, Biological; NF-kappa B - metabolism; NF-κB protein; p38 Mitogen-Activated Protein Kinases - metabolism; Pathways; Pharmacology; Phosphorylation; Piperazines - pharmacology; Protein Transport; Protein-tyrosine kinase; Proto-Oncogene Proteins c-abl - genetics; Proto-Oncogene Proteins c-abl - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; Sensitizing; Signal transduction; Signal Transduction - drug effects; Signaling; Skin cancer; Stat3 protein; STAT3 Transcription Factor - metabolism; Survival; Tumors; Tyrosine; United States > US; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055509

Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.