Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters

Mi, Yan Jun; Liang, Yong; Hong, Huixiao; Zhao, Hong; Wu, Chung Pu; Wang, Fang; Tao, Liyuan; Zhang, Chuan Zhao; Dai, Chun Ling; Tiwari, Amit K.; Xu, Xiao; To, Kenneth K.W.; Ambudkar, Suresh V.; Chen, Zhe‐Sheng; Li, Fu

doi:10.1158/0008-5472.can-10-0111

Cited by 301 publications

(277 citation statements)

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“…It was also demonstrated that PR -luminal B tumors that were treated with neoadjuvant chemotherapy (adriamycin/cyclophosphamide) (70). c Apatinib (YN968D1) is a small-molecule TKI that inhibits VEGFR2 (Flk-1/KDR), RET (rearranged during transfection), c-Kit (stem cell factor receptor) and c-Src tyrosine kinases (142). HER, human epidermal growth factor receptor; ER, estrogen receptor; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; FGF, fibroblast growth factor receptor; IGF, insulin-like growth factor; PI3K, phosphatidylinositol-3-kinase; mTOR, mammalian target of rapamycin; PDK, phosphoinositide-dependent kinase; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; FLT, FMS-like tyrosine kinase; TKI, tyrosine kinase inhibitor.…”

Section: Luminal B Subtype Breast Cancer Therapeutic Potentialsmentioning

confidence: 99%

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

et al. 2013

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Abstract. In this review, the advances in the study of breast cancer molecular classifications and the molecular signatures of the luminal subtypes A and B of breast cancer were summarized. Effective clinical outcomes depend mainly on successful preclinical diagnosis and therapeutic decisions. Over the last few years, the ever-expanding investigations focusing on breast cancer diagnosis and the clinical trials have provided accumulating information on the molecular characteristics of breast cancer. Specifically, among the estrogen receptor (ER)-positive types of breast cancer, the luminal subtype A breast cancer has been shown to exhibit good clinical outcomes with endocrine therapy, whereas the luminal subtype B breast cancer represents the more complicated type, diagnostically as well as therapeutically. Furthermore, even in luminal subtype A breast cancer, the resistance to treatment has become the major limitation for endocrine-based therapy. Accumulating molecular data and further clinical trials may enable more accurate diagnostic and therapeutic decisions. The molecular signatures have emerged as a powerful tool for future diagnosis and therapeutic decisions, although currently available data are limited.

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Section: Luminal B Subtype Breast Cancer Therapeutic Potentialsmentioning

confidence: 99%

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

et al. 2013

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“…Inhibition kinetics of sorafenib on intracellular mitoxantrone (ABCG2 substrate) efflux by ABCG2 was detected as previous described (6). Briefly, HEK293/ABCG2 cells were incubated with mitoxantrone (2.5-20 mmol/L in final) at 37 C for 30 minutes.…”

Section: Drug Accumulation and In Vitro Transport Assaysmentioning

confidence: 99%

“…The intracellular concentration of drug was determined by FACS. The quantity of drug efflux by ABCG2 was calculated by subtracting the values obtained at 37 C from those at 0 C. The inhibitory effect of sorafenib was analyzed using Lineweaver-Burk plots as previously described (6).…”

Section: Drug Accumulation and In Vitro Transport Assaysmentioning

confidence: 99%

“…It would not be surprising if clinical use of ABCG2 inhibitors with novel chemical structures may have unexpected effects due to several problems, such as toxicity or safety and pharmacokinetic uncertainty of the compound. Although most small molecule tyrosine kinase inhibitors (TKI) are competitive or high-affinity substrates of ABCG2 (5), some of them, such as apatinib (6), sunitinib (7), lapatinib (8), erlotinib (9), gefitinib (10), imatinib (11), nilotinib (12), and vandetanib (13), have been reported to be inhibitors or modulators. These TKIs seem to inhibit the function of ABCG2 transporter by directly interacting with this transporter, thereby completely reversing the MDR of cancer cells (14).…”

Section: Introductionmentioning

confidence: 99%

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New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Wei

Zhao

et al. 2012

Molecular Cancer Therapeutics

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Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy.

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“…However, many of these inhibitors failed to be utilized in clinical application due to the unacceptable toxicity as well as problematic pharmacokinetic interactions (4). But recently, we have reported that several TKIs, including lapatinib, erlotinib, apatinib, and afatinib, can overcome MDR mediated by ABC transporters (25)(26)(27)(28)(29)(30). And the preliminary results with inhibitors showed no appreciable impacts on cytochrome P4503A4 drug metabolism and no significant drug interactions with common chemotherapeutic agents, offering new hope for combination therapy in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1-and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1-or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [ 125 I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1-and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic.

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Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters

Cited by 301 publications

References 50 publications

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

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