Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

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.

AC-93253 triggers the downregulation of melanoma progression markers and the inhibition of melanoma cell proliferation

“…We postulate that this result is consistent with several intrinsic resistance mechanisms to doxorubicin that are present in the melanoma cell line and with the SIRT2 inhibitor weakening one or more resistance factor by decreasing the expression of the responsible gene(s) (e.g., doxorubicin transporters from the ABC superfamily) either directly or by influencing the expression of an intermediate regulator. Analogous narrow response curve-shifting results for melanoma cells in vitro have been described in the literature for treatments postulated to have inhibitory effects on resistance factors, e.g., ABCB5-blocking antibodies [56] or imatinib, which directly inhibits the ABCB1 transporter and blocks signaling pathways that upregulate the ABCB1 transporter and other transporters [57].…”

Melatonin: an inhibitor of breast cancer

“…Although the majority of this work will be discussed below in the section entitled “Melatonin: a regulator of resistance to endocrine and drug therapy,” this study clearly demonstrates that dLEN via its repression of the nocturnal circadian melatonin signal promotes tumor aerobic glycolysis (Warburg effect) and the expression and/or phospho-activation of key signaling pathways and nodes involved in tumor proliferation and survival that drive resistance in breast cancer cells to endocrine and chemo-therapies. These signaling pathways induced by dLEN include the PI3K/AKT pathway, the EGFR/HER2 and downstream RAS/MAPK/ERK pathways, the p21 activating kinase 1 (PAK1), and PI3K/AKT/pyruvate dehydrogenase kinase one (PDK1)/mTOR/p90 ribosomal S6 kinase (RSK) family members, all of which can drive cancer cells to proliferation, survival, drug resistance, and metastasis (Lee et al 1992; McCubrey et al 2007; Li et al 2008; Romeo et al 2012; Sims et al 2013; Roskoski 2014). …”

Multifunctional Abl kinases in health and disease

“…In breast cancer cells, doxorubicin induces an atypical activation of NF-κB through ABL1 kinase activity but, treatment with the ABL inhibitor imatinib in combination with this chemotherapy drug reversed intrinsic and acquired resistance, and significantly enhanced apoptosis of breast cancer cells (Esparza-Lopez et al, 2013;Sims et al, 2013). In estrogen receptor (ER)-positive breast cancer cells, ABL is a functional partner of ERs, and inhibition of ABL resulted in sensitization to anti-estrogen therapies with tamoxifen, fulvestrant and aromatase inhibitors (Esparza-Lopez et al, 2013;Weigel et al, 2013;Zhao et al, 2011Zhao et al, , 2010.…”