Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

• Published in: Cellular physiology and biochemistry Vol. 45; no. 4; pp. 1515 - 1528
• Main Authors: Gupta, Pranav, Zhang, Yun-Kai, Zhang, Xiao-Yu, Wang, Yi-Jun, Lu, Kimberly W., Hall, Timothy, Peng, Richard, Yang, Dong-Hua, Xie, Ni, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: ABCB1; ABCG2; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; ATP-binding cassette transporters; Benzopyrans - chemistry; Benzopyrans - pharmacology; Binding Sites; Breast cancer; Cancer therapies; Cell Line, Tumor; Cell Survival - drug effects; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - metabolism; Cytotoxicity; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - drug effects; HEK293 Cells; Humans; Imino Furanoses - chemistry; Imino Furanoses - pharmacology; Kinases; Mitoxantrone - pharmacology; Molecular Docking Simulation; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Mutation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Original Paper; Paclitaxel - pharmacology; Penicillin; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; Voruciclib; Voruciclib; ATP-binding cassette transporters; ABCB1; Multidrug resistance; ABCG2
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000487578

Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.