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The multi-targeted tyrosine kinase inhibitor SKLB610 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs

Year: 2022
Type: article
Abstract: The overexpression of ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in cancer cells is frequently associated with the development of multidrug resistance (MDR) in cancer patients, which remains a major obstacle to effective cancer treatment. By utilizing energy derived from ATP hydrolysis, both transporters have been shown to reduce the chemosensitivity of cancer cells by actively effluxing cytotoxic anticancer drugs out of cancer cells. Knowing that there are presently no approved drugs or other therapeutics for the treatment of multidrug-resistant cancers, in recent years, studies have investigated the repurposing of tyrosine kinase inhibitors (TKIs) to act as agents against MDR mediated by ABCB1 and/or ABCG2. SKLB610 is a multi-targeted TKI with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor 2 (FGFR2). In this study, we investigate the interaction of SKLB610 with ABCB1 and ABCG2. We discovered that neither ABCB1 nor ABCG2 confers resistance to SKLB610, but SKLB610 selectively sensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents in a concentration-dependent manner. Our data indicate that SKLB610 reverses ABCG2-mediated MDR by attenuating the drug-efflux function of ABCG2 without affecting its total cell expression. These findings are further supported by results of SKLB610-stimulated ABCG2 ATPase activity and in silico docking of SKLB610 in the drug-binding pocket of ABCG2. In summary, we reveal the potential of SKLB610 to overcome resistance to cytotoxic anticancer drugs, which offers an additional treatment option for patients with multidrug-resistant cancers and warrants further investigation.
DOI: 10.1016/j.biopha.2022.112922
Authors: Chung-Pu Wu, Megumi Murakami, Yu-Shan Wu, Chun-Ling Lin, Yan-Qing Li, Yang-Hui Huang, Tai-Ho Hung, Suresh V. Ambudkar
Institutions: Chang Gung University, Chang Gung Memorial Hospital, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Tunghai University, Keelung Chang Gung Memorial Hospital
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,740
Funders: Chang Gung Memorial Hospital, Chang Gung Medical Foundation, Ministry of Science and Technology, Taiwan, Chang Gung Memorial Hospital, Linkou, National Institutes of Health, National Cancer Institute
Awards: G2962109343, G3240529281, G3890728273, G521149998, G5322946715, Investigation on the Role of Placental Soluble Epoxide Hydrolase in Pregnancies Complicated by Pre-Gestational and Gestational Diabetes Mellitus, G5966451722, G6857687008, G737106015, G7762680530, G8004836276, A Systematic Approach to Identify Novel Inhibitors of Multidrug-Resistance Associated Proteins from Purified Natural Products: Drug Screening, in Vitro and in Vivo Model Systems, Biochemical Analysis of Multidrug Resistance-linked Transport Proteins
OpenAlex ID: W4223597500
FWCI: 0.813
Cites: 96
Cited by: 11
Related to: 10