“…Conflicting results have been published regarding the ability of BCRP to transport this compound. In one study, overexpression of BCRP in Saos2 cells did not confer resistance to imatinib, and accumulation and efflux of this drug were not affected by BCRP expression and ATP depletion (Houghton et al, 2004), suggesting that imatinib is not a substrate of BCRP. Rather, imatinib may serve as a potent BCRP inhibitor thereby enabling reversal of BCRP-mediated resistance to topotecan and SN-38 (Houghton et al, 2004).…”
Section: Imatinibmentioning
confidence: 99%
“…In one study, overexpression of BCRP in Saos2 cells did not confer resistance to imatinib, and accumulation and efflux of this drug were not affected by BCRP expression and ATP depletion (Houghton et al, 2004), suggesting that imatinib is not a substrate of BCRP. Rather, imatinib may serve as a potent BCRP inhibitor thereby enabling reversal of BCRP-mediated resistance to topotecan and SN-38 (Houghton et al, 2004). Similarly, accumulation of mitoxantrone in primary chronic myeloid leukaemia (CML) CD34 þ cells overexpressing BCRP was significantly increased by 5 mM of imatinib, confirming the activity of this TKI as a BCRP inhibitor (Jordanides et al, 2006).…”
Multidrug resistance is often associated with the (over)expression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. This minireview discusses the role of one selected ABC-transporter family member, the breast cancer resistance protein (BCRP/ABCG2), in the (pre)clinical efficacy of novel experimental anticancer drugs, in particular tyrosine kinase inhibitors.
“…Conflicting results have been published regarding the ability of BCRP to transport this compound. In one study, overexpression of BCRP in Saos2 cells did not confer resistance to imatinib, and accumulation and efflux of this drug were not affected by BCRP expression and ATP depletion (Houghton et al, 2004), suggesting that imatinib is not a substrate of BCRP. Rather, imatinib may serve as a potent BCRP inhibitor thereby enabling reversal of BCRP-mediated resistance to topotecan and SN-38 (Houghton et al, 2004).…”
Section: Imatinibmentioning
confidence: 99%
“…In one study, overexpression of BCRP in Saos2 cells did not confer resistance to imatinib, and accumulation and efflux of this drug were not affected by BCRP expression and ATP depletion (Houghton et al, 2004), suggesting that imatinib is not a substrate of BCRP. Rather, imatinib may serve as a potent BCRP inhibitor thereby enabling reversal of BCRP-mediated resistance to topotecan and SN-38 (Houghton et al, 2004). Similarly, accumulation of mitoxantrone in primary chronic myeloid leukaemia (CML) CD34 þ cells overexpressing BCRP was significantly increased by 5 mM of imatinib, confirming the activity of this TKI as a BCRP inhibitor (Jordanides et al, 2006).…”
Multidrug resistance is often associated with the (over)expression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. This minireview discusses the role of one selected ABC-transporter family member, the breast cancer resistance protein (BCRP/ABCG2), in the (pre)clinical efficacy of novel experimental anticancer drugs, in particular tyrosine kinase inhibitors.
“…However, the neurotoxicity of fumitremorgin C prevents its use in vivo (34). Some clinically used tyrosine kinase inhibitors such as gefitinib and imatinib have also been shown to inhibit BCRP (8,35). However, they have intrinsic anticancer activity.…”
Section: Enhancing Effect Of Yho-13351 On Antitumor Activity Of Irinomentioning
Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRPtransduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.
“…Imatinib, a tyrosine kinase inhibitor, is a promising molecularly targeted chemotherapeutic agent. It has been shown to be both a substrate and inhibitor of ABCG2, thus allowing its efflux by a stem cell that express this ABC transporter (Houghton et al, 2004;Burger et al, 2004). In-depth mechanistic studies in imatinib-resistant leukemia cells revealed several "acquired" mutations in the kinase domain of ABL in patient with CML or with AML associated with t(9;22)(q34;q11).…”
Section: Working Models Of Cancer Drug Resistancementioning
confidence: 99%
“…TKIs are an important new class of molecularly targeted chemotherapeutic agents that specifically inhibit several oncogenic tyrosine kinases, thereby regulating cancer proliferation, invasion, metastasis and angiogenesis. The first TKI that was approved for CML, imatinib, has been shown to reverse MDR by inhibiting ABCB1(Pgp) (Hegedus et al, 2002) and ABCG2 (Houghton et al, 2004). A few other TKIs were also demonstrated to reverse drug resistance mediated by MDR transporters in various in vitro and in vivo models (reviewed in Wang & Fu, 2010).…”
Section: Novel Transporter Inhibitors May Hold Promise To Target Cscsmentioning
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.