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

University of Kentucky, United States of America
PLoS ONE (Impact Factor: 3.23). 01/2013; 8(1):e55509. DOI: 10.1371/journal.pone.0055509
Source: PubMed


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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    • "Nilotinib, an imatinib derivative, inhibits the activity of both ABCG2 and ABCB1, leading to enhanced DXR accumulation. Different cells may behave in opposite ways because imatinib has been reported to increase DXR concentration and synergize cytotoxicity in breast cancer cells [31] but not in sarcoma cells [28], [32]. The concentration of the drug in the cell is not likely solely to explain the outcome, because, for example, raising the concentration of the drug does not lead to such a profound p53 accumulation and activity as seen with the MX + imatinib combination (data not shown). "
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    ABSTRACT: Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX) and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The difference in MX and doxorubicin was related to significant augmentation of DNA damage. Transcriptionally active p53 accumulated in cells in which human papillomavirus E6 normally degrades p53. The combination treatment resulted in caspase activation and apoptosis, but this effect did not depend on either p53 or p73 activity. Despite increased p53 activity, the cells arrested in G2 phase became defective in this checkpoint, allowing cell cycle progression. The effect after MX treatment depended partially on c-Abl: Short interfering RNA knockdown of c-Abl rendered HeLa cells less sensitive to MX. The effect of imatinib was decreased by c-Abl siRNA suggesting a role for catalytically inactive c-Abl in the death cascade. These findings indicate that MX has a unique cytotoxic effect when the kinase activity of c-Abl is inhibited. The treatment results in increased DNA damage and c-Abl-dependent apoptosis, which may offer new possibilities for potentiation of cancer chemotherapy.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "While 0.5 hr NVP-BEZ235 seems to have little effect on GSK3β phosphorylation, prolonged exposure to doxorubicin leads to an enhanced GSK3β phosphorylation, suggesting increased PI3K/Akt signaling activity. This is in line with previous data that show doxorubicin to be an activator of the PI3K/Akt pathway [35], [36], [37]. Next we immunoprecipitated GSK3β from cells treated with doxorubicin or cells treated with the posttreatment combination (Fig. 5D). "
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    ABSTRACT: Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ∼30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3β and inhibition of GSK3β, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.
    Full-text · Article · Dec 2013 · PLoS ONE
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    ABSTRACT: Resistance to apoptosis is a major obstacle preventing effective therapy for malignancies. Bcl-2 plays a significant role in inhibiting apoptosis. We reconstructed a stable human Bcl-2 transfected cell line, BIU87- Bcl-2, that was derived from the transfection of human bladder carcinoma cell line BIU87 with a plasmid vector containing recombinant Bcl-2 [pcDNA3.1(+)-Bcl-2]. A cell line transfected with the plasmid alone [pcDNA3.1(+)- neo] was also established as a control. BIU87 and BIU87-neo proved sensitive to adriamycin induced apoptosis, while BIU87-Bcl-2 was more resistant. In view of the growing evidence that NF-κB may play an important role in regulating apoptosis, we determined whether Bcl-2 could modulate the activity of NF-κB in bladder carcinoma cells. Stimulation of BIU87, BIU87-neo and BIU87-Bcl-2 with ADR resulted in an increase expression of NF-κB (p<0.001). The expression of NF-κB in BIU87-Bcl-2 was higher than in the other two cases, with a concomitant reduction in the IκBκ?protein level. These results suggest that the overexpression of Bcl-2 renders human bladder carcinoma cells resistant to adriamycin -induced cytotoxicity and there is a link between Bcl-2 and the NF-κB signaling pathway in the suppression of apoptosis.
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