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Cited by 121Drug Transport and Resistance MechanismsCancer Cells and MetastasisCell death mechanisms and regulation

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

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Sims, Jonathan T., Ganguly, Sourik S., Bennett, Holly, Friend, J. Woodrow, Tepe, Jessica, Plattner, Rina·2013·PLoS ONE
DOI 10.1371/journal.pone.0055509PMC PMC3561297
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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.

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  • STAT3 is implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition restores sensitivity of tumors to chemotherapeutic drugs.

    “STAT3 has been implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Sims et al., 2013

    The Results section (‘Imatinib potentiates doxorubicin-induced apoptosis by inhibiting STAT3-dependent survival pathways’; page unavailable) says STAT3 is implicated in chemoresistance and reports that silencing STAT3 enhanced doxorubicin-induced apoptosis in cancer cells. It does not establish a strong correlation between STAT3 activation and chemoresistance, and its cell-based doxorubicin findings do not demonstrate restored sensitivity of tumors to chemotherapeutic drugs generally. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Sims, J. T., Ganguly, S. S., Bennett, H., Friend, J. W., Tepe, J., & Plattner, R.
Affiliations
University of Kentucky (US)
Corresponding author
Plattner, Rina
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-01-31
Volume
8
Issue
1
Pages
e55509
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0055509
PMC
PMC3561297
OpenAlex
W1964709116
Cited by
121
References
3
Citations by year
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FWCI
5.89
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Ohio State University
  • National Institutes of Health
  • National Cancer Institute (R01CA116784)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
imatinib, doxorubicin resistance, anthracycline resistance, c-Abl, Arg kinase, STAT3, NF-κB, HSP27, p38 MAPK, Akt signaling, P-glycoprotein, multidrug resistance, G2/M cell cycle arrest, apoptosis, metastatic cancer, efflux pumps
MeSH terms
Imatinib Mesylate, Antineoplastic Agents, Benzamides, Cell Survival, Doxorubicin, Humans, Models, Biological, Piperazines, Pyrimidines, Signal Transduction, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-abl, NF-kappa B, Apoptosis, ATP Binding Cassette Transporter, Subfamily B, Drug Resistance, Neoplasm, ATP Binding Cassette Transporter, Subfamily B, Member 1, Protein Transport, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, HSP27 Heat-Shock Proteins, G2 Phase Cell Cycle Checkpoints, M Phase Cell Cycle Checkpoints

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