Novel Acrylonitrile Derivatives, YHO-13177 and YHO-13351, Reverse BCRP/ABCG2-Mediated Drug Resistance<i>In Vitro</i>and<i>In Vivo</i>

Yamazaki, Ryuta; Nishiyama, Yoshikazu; Furuta, Tomio; Hatano, Hiroshi; Igarashi, Yoshiaki; Asakawa, Naoyuki; Kodaira, Hiroshi; Takahashi, Hiroyuki; Aiyama, Ritsuo; Matsuzaki, Takeshi; Yagi, Nao; Sugimoto, Yoshikazu

doi:10.1158/1535-7163.mct-10-0874

Cited by 42 publications

(25 citation statements)

References 30 publications

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“…However, there still have 20–30% of NSCLC patients with amplified wild-type EGFR (wt-EGFR), which remain responsive to EGFR TKIs [Cappuzzo et al, 2005; Tsao et al, 2005]. In our study, we have shown that NCI-H460 cells intrinsically express low level of ABCG2, which was consistent with previous studies [Robey et al, 2001; Yamazaki et al, 2011], and consistent with other studies which have found that ABCG2 was up-regulated in tumor-initiating cells and directly correlated with the chemosensitivity in NSCLC [Gottschling et al, 2012; Yoh et al, 2004]. Furthermore, ABCG2-overexpressing patients had shorter progression-free survival and overall decreased survival in patients with advanced NSCLC [Yoh et al, 2004].…”

Section: Discussionsupporting

confidence: 91%

ARRY‐334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP‐Binding Cassette Subfamily G Member 2

Wang

Patel

Sim

et al. 2014

J of Cellular Biochemistry

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Background ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Methods Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Results Our results demonstrate that ARRY-334543 (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity towards ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentration did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. Conclusion We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2.

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Section: Discussionsupporting

confidence: 91%

ARRY‐334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP‐Binding Cassette Subfamily G Member 2

Wang

Patel

Sim

et al. 2014

J of Cellular Biochemistry

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“…It indicates that increase in MX levels in the cells expressing ABCG2 is because of inhibition of ABCG2 drug efflux function by telatinib. Some selective ABCG2 inhibitors, such as acrylonitrile derivatives, YHO-13177 and YHO-13351, have been reported to inhibit the function well as expression of ABCG2 [45]. Drugs such as LY294002 (PI3K inhibitor) [46] SGI-1776 (PIM-1 kimase inhibitor) [47] telmisartan and rosiglitazone (PPAR-Y antagonists) [48] were reported to alter the membrane localization of ABCG2 transporter.…”

Section: Discussionmentioning

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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“…Several identified BCRP substrates are substrates at lower concentrations and inhibitors at higher concentrations. In addition to the fumitremorgin C (FTC) analogues that were found to be specific inhibitors of BCRP, several novel classes of compounds such as poloxamines and acrylonitrile derivatives are emerging as potent BCRP inhibitors [26–29]. In addition, BCRP function is also inhibited by the tyrosine kinase inhibitor imatinib mesylate [30] but not by phosphodiesterase-5 inhibitors as is Pgp/ABCB1 [31].…”

Section: Section 2 Background: Bcrp In Cancer Drug Resistancementioning

confidence: 99%

Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

Natarajan¹,

Xie²,

Baer³

et al. 2012

Biochemical Pharmacology

343

273

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Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.

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Novel Acrylonitrile Derivatives, YHO-13177 and YHO-13351, Reverse BCRP/ABCG2-Mediated Drug ResistanceIn VitroandIn Vivo

Cited by 42 publications

References 30 publications

ARRY‐334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP‐Binding Cassette Subfamily G Member 2

ARRY‐334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP‐Binding Cassette Subfamily G Member 2

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

Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

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