Apoptozole Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer

• Kang-Yao Zeng

  Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China

• Qing-Yi Zhou

  Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China

• Yun-Xi Zhang

  Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China

• Zhe-Sheng Chen

  Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, New York 11432, USA

• Zhi Shi

  Department of Cell Biology & Institute of Biomedicine, Guangdong Provincial Biotechnology & Engineering Technology Research Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Genomic Medicine Engineering Research Center of Ministry of Education, MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China

• Song-Wang Cai

  Department of Thoracic Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China

Lung cancer is a widespread malignant tumor with a highmortality rate, often difficult to treat effectively due to chemoresistance. Given the close association between ABCG2 overexpression and cancer multidrug resistance, overcoming the issue of MDR caused by ABCG2 is still a challenge. In this study, we found that the small molecule apoptozole effectively suppresses the transport activity of ABCG2, thus mitigating multidrug resistance in lung cancer cells, overexpressing ABCG2, and improving the therapeutic effects of chemotherapy drugs mitoxantrone and topotecan. Additionally, apoptozole does not affect the expression level of ABCG2 protein. Molecular docking studies have demonstrated that apoptozole can firmly bind to the binding pocket of ABCG2. Our data present that apoptozole is an ABCG2 inhibitor and modulates ABCG2-mediated multidrug resistance in lung cancer.

Fan J, To KKW, Chen ZS, Fu L. ABC transporters affects tumor immune microenvironment to regulate cancer immunotherapy and multidrug resistance. Drug Resist Updat 2023; 66: 100905.

Li W, Zhang H, Assaraf YG, Zhao K, Xu X, Xie J, et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resist Updat 2016; 27: 14-29.

Sun YL, Kathawala RJ, Singh S, Zheng K, Talele TT, Jiang WQ, et al. Zafirlukast antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Anticancer Drugs 2012; 23: 865-873.

Wang DS, Patel A, Sim HM, Zhang YK, Wang YJ, Kathawala RJ, et al. ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2/ J Cell Biochem 2014; 115: 1381-1391.

Doyle L, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22: 7340-7358.

Bates SE, Robey R, Miyake K, Rao K, Ross DD, Litman T. The role of half-transporters in multidrug resistance. J Bioenerg Biomembr 2001; 33: 503-511.

van Hoppe S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation. Pharmacol Res 2017; 120: 43-50.

van Hoppe S, Jamalpoor A, Rood JJM, Wagenaar E, Sparidans RW, Beijnen JH, et al. Brain accumulation of osimertinib and its active metabolite AZ5104 is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Pharmacol Res 2019; 146: 104297.

Liu K, Li YC, Chen Y, Shi XB, Xing ZH, He ZJ, et al. AZ32 Reverses ABCG2-Mediated Multidrug Resistance in Colorectal Cancer. Front Oncol 2021; 11: 680663.

Wang JQ, Teng QX, Lei ZN, Ji N, Cui Q, Fu H, et al. Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor. Front Cell Dev Biol 2020; 8: 601400.

Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H. Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations. Front Pharmacol 2016; 7: 518.

Yu ZZ, Xu BQ, Wang YY, Zhang PW, Shu YB, Shi Z. GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs. Biomedicines 2023; 11.

Liu K, Chen Y, Shi XB, Xing ZH, He ZJ, Wang ST, et al. Inhibiting the Activity of ABCG2 by KU55933 in Colorectal Cancer. Recent Pat Anticancer Drug Discov 2022; 17: 387-395.

Wang J, Wang JQ, Cai CY, Cui Q, Yang Y, Wu ZX, et al. Reversal Effect of ALK Inhibitor NVP-TAE684 on ABCG2-Overexpressing Cancer Cells. Front Oncol 2020; 10: 228.

Yang Y, Wu ZX, Wang JQ, Teng QX, Lei ZN, Lusvarghi S, et al. OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance. Front Pharmacol 2021; 12: 620874.

Narayanan S, Fan YF, Gujarati NA, Teng QX, Wang JQ, Cai CY, et al. VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In vitro and In vivo Study. Cancers (Basel) 2021; 13.

Lei ZN, Teng QX, Zhang W, Fan YF, Wang JQ, Cai CY, et al. Establishment and Characterization of a Topotecan Resistant Non-small Cell Lung Cancer NCI-H460/TPT10 Cell Line. Front Cell Dev Biol 2020; 8: 607275.

Zhang WJ, Li Y, Wei MN, Chen Y, Qiu JG, Jiang QW, et al. Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer. Cancer Lett 2017; 386: 100-109.

Williams DR, Ko SK, Park S, Lee MR, Shin I. An apoptosis-inducing small molecule that binds to heat shock protein 70. Angew Chem Int Ed Engl 2008; 47: 7466-7469.

Cho HJ, Gee HY, Baek KH, Ko SK, Park JM, Lee H, et al. A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator. J Am Chem Soc 2011; 133: 20267-20276.

Ko SK, Kim J, Na DC, Park S, Park SH, Hyun JY, et al. A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities. Chem Biol 2015; 22: 391-403.

Cho HJ, Kim GH, Park SH, Hyun JY, Kim NK, Shin I. Probing the effect of an inhibitor of an ATPase domain of Hsc70 on clathrin-mediated endocytosis. Mol Biosyst 2015; 11: 2763-2769.

Baek KH, Zhang H, Lee BR, Kwon YG, Ha SJ, Shin I. A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens Sci Rep 2015; 5: 17642.

Lin QC, Wang J, Wang XL, Pan C, Jin SW, Char S, et al. Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 167137.

Jiang W, Tie Z, Yu C, Chen Y, Liu D, Li B. An engineered nanoplatform inhibiting energy metabolism and lysosomal activity of tumor cells to multiply cisplatin-based chemotherapy. Biomaterials 2023; 302: 122354.

Cui X, Liang Z, Lu J, Wang X, Jia F, Hu Q, et al. A multifunctional nanodiamond-based nanoplatform for the enhanced mild-temperature photothermal/chemo combination therapy of triple negative breast cancer via an autophagy regulation strategy. Nanoscale 2021; 13: 13375-13389.

• PDF

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.