GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance

Sodani, Kamlesh; Tiwari, Amit K.; Singh, Satyakam; Patel, Atish; Xiao, Zhijie; Chen, Jun-Jiang; Sun, Yulin; Talele, Tanaji T.; Chen, Zhe‐Sheng

doi:10.1016/j.bcp.2012.02.028

Cited by 55 publications

(44 citation statements)

References 47 publications

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“…In this study, we discovered that tyrphostin RG14620 increased the accumulation of PhA by inhibiting the efflux function of ABCG2 in the same manner as other EGFR inhibitors that interact with the ABC drug transporters ABCB1 and ABCG2 [44, 45, 50]. However, tyrphostin RG14620 is selective for ABCG2 relative to ABCB1 and ABCC1.…”

Section: Discussionmentioning

confidence: 99%

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Hsiao

Murakami

et al. 2017

Cancer Letters

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The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Hsiao

Murakami

et al. 2017

Cancer Letters

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“…The accumulation of [ 3 H]-paclitaxel in KB-3-1 and KB-C2 cells was measured in the absence or presence of motesanib at 1 µM and 3 µM, and verapamil at 3 µM [45]. Cells were trypsinized and four aliquots from each cell line were resuspended in the DMEM medium in four centrifuge tubes.…”

Section: Methodsmentioning

confidence: 99%

“…In the efflux study cells were also incubated with 0.01 µM [ 3 H]-paclitaxel according to the method used in the accumulation study [45]. However, after washing three times with ice cold PBS, the suspended cells were incubated at 37°C in fresh DMEM medium with or without reversal drugs.…”

Section: Methodsmentioning

confidence: 99%

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Wang

Kathawala

Zhang

et al. 2014

Biochemical Pharmacology

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Cancer cells often become resistant to chemotherapy through a phenomenon known as multidrug resistance (MDR). Several factors are responsible for the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP binding cassette (ABC) transporters. Some small molecule tyrosine kinase inhibitors (TKIs) were recently reported to modulate the activity of ABC transporters. Therefore, the purpose of this study was to determine if motesanib, a multikinase inhibitor, could reverse ABCB1-mediated MDR. The results showed that motesanib significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Motesanib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant change in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 3 µM motesanib for 72 h. Moreover, motesanib stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, the docking studies indicated favorable binding of motesanib within the transmembrane region of homology modeled human ABCB1. Here, we report for the first time, motesanib, at clinically achievable plasma concentrations, antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings may be useful for cancer combination therapy with TKIs in the clinic.

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“…The low-energy 3D structures of telatinib were generated by LigPrep v2.3 as described previously. Conformational search on LigPrep generated ligand structure was performed as per previous study [28]. …”

Section: Methodsmentioning

confidence: 99%

Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo

Sodani

Patel

Anreddy

et al. 2014

Biochemical Pharmacology

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Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15 mg/kg) with doxorubicin (1.8 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.

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GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance

Cited by 55 publications

References 47 publications

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo

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