BACKGROUND AND PURPOSEPelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up-regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem-like cells responsible for cancer recurrence. EXPERIMENTAL APPROACHAlterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization. KEY RESULTSWhile pelitinib did not modulate ABCB1/ABCG2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB1-and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells. CONCLUSIONS AND IMPLICATIONSThis study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia. AbbreviationsABC, ATP-binding cassette; CSC, cancer stem-like cell; FTC, fumitremorgin C; HSE, heat shock element; MDR, multidrug resistance; NSP, non-SP population; PhA, pheophorbide A; Rh123, rhodamine 123; SP, side population BJP IntroductionThe large family of ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1/P-gp), ABCC1/MRP1 and ABCG2, play a key role in the energy-dependent cellular efflux of chemotherapeutic drugs. They are capable of recognizing and extruding a broad range of structurally and functionally unrelated anticancer drugs, thereby leading to multidrug resistance (MDR) in cancer cells. Cancer recurrence is a major hurdle hindering successful chemotherapy. It is believed to arise from the survival of cancer stem-like cells (CSCs) after anticancer treatment. To this end, cancer stemlike phenotypes are correlated with elevated expression of the efflux transporters ABCB1 and/or ABCG2 (Ho et al., 2007), which protect the cancer cells from chemotherapy. Therefore, substantial research efforts have been made to target these CSCs to eliminate metastasis and prevent recurrence (Frank et al., 2010;Takebe et al., 2011). TK inhibitors (TKI...
However, the most common mechanism of resistance is the active efflux of drugs by ATP-binding cassette (ABC) transporters including P-glycoprotein (ABCB1/P-gp), ABCC1/ MRP1 and ABCG2 [6]. These transporters play a key role in the energy-dependent cellular efflux of toxic agents. They are capable of recognizing and extruding a broad range of functionally and structurally unrelated compounds, thereby causing the MDR phenotype in various cancer types. An obvious strategy to restore drug sensitivity in MDR cancer cells caused by ABC drug transporters is to block transporter-mediated drug efflux. Over the past decade, tremendous efforts have been made to discover and synthesize such inhibitors/modulators. Numerous clinical trials have been performed to evaluate the combination of ABCB1/P-gp modulators with standard chemotherapy regimens in enhancing anticancer efficacy [7]. However, none of them has been successfully put into clinical use, partly because of their low potency and lack of specificity
Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.
We have recently reported that vatalanib, an orally active small molecule multi-tyrosine kinase inhibitor (Hess-Stumpp et al., 2005 [1]), can sensitize multidrug resistant (MDR) colon cancer cells to chemotherapy under hypoxia by inhibiting two MDR transporters ABCB1 and ABCG2 (To et al., 2015 [2]). This data article describes the possible circumvention of resistance to specifically platinum (Pt)-based anticancer drugs by vatalanib via inhibition of two other efflux transporters ABCC2 and ATP7A. Data from the flow cytometric transporter efflux assay showed specific inhibition of ABCC2 activity by vatalanib in stable transfected cells and ABCC2-overexpressing oxaliplatin-resistant colon cancer cells HCT116/Oxa. We also performed the transporter ABCC2 ATPase assay and showed an increase in ATP hydrolysis by ABCC2 in the presence of vatalanib. ATP7A mRNA expression was also shown to be upregulated in HCT116/Oxa cells. Vatalanib was shown to suppress this upregulated ATP7A expression. Data from the cellular Pt accumulation assay showed a lower Pt accumulation in HCT116/Oxa cells than the parental sensitive HCT116 cells. Vatalanib was shown to increase cellular Pt accumulation in a concentration-dependent manner. Combination of oxaliplatin and vatalanib was shown to restore the suppressed apoptosis in HCT116/Oxa cells.
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