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Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1.
PLoS One. 2013; 8(1):e55509.Plos

Abstract

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.

Authors+Show Affiliations

Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, Kentucky, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23383209

Citation

Sims, Jonathan T., et al. "Imatinib Reverses Doxorubicin Resistance By Affecting Activation of STAT3-dependent NF-κB and HSP27/p38/AKT Pathways and By Inhibiting ABCB1." PloS One, vol. 8, no. 1, 2013, pp. e55509.
Sims JT, Ganguly SS, Bennett H, et al. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE. 2013;8(1):e55509.
Sims, J. T., Ganguly, S. S., Bennett, H., Friend, J. W., Tepe, J., & Plattner, R. (2013). Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PloS One, 8(1), e55509. https://doi.org/10.1371/journal.pone.0055509
Sims JT, et al. Imatinib Reverses Doxorubicin Resistance By Affecting Activation of STAT3-dependent NF-κB and HSP27/p38/AKT Pathways and By Inhibiting ABCB1. PLoS ONE. 2013;8(1):e55509. PubMed PMID: 23383209.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. AU - Sims,Jonathan T, AU - Ganguly,Sourik S, AU - Bennett,Holly, AU - Friend,J Woodrow, AU - Tepe,Jessica, AU - Plattner,Rina, Y1 - 2013/01/31/ PY - 2012/11/02/received PY - 2012/12/23/accepted PY - 2013/2/6/entrez PY - 2013/2/6/pubmed PY - 2013/7/19/medline SP - e55509 EP - e55509 JF - PloS one JO - PLoS ONE VL - 8 IS - 1 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23383209/Imatinib_reverses_doxorubicin_resistance_by_affecting_activation_of_STAT3_dependent_NF_κB_and_HSP27/p38/AKT_pathways_and_by_inhibiting_ABCB1_ L2 - http://dx.plos.org/10.1371/journal.pone.0055509 DB - PRIME DP - Unbound Medicine ER -