Apoptozole Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer

Kang-Yao  Zeng; Qing-Yi  Zhou; Yun-Xi  Zhang; Zhe-Sheng  Chen; Zhi  Shi; Song-Wang  Cai

doi:10.30683/1929-2279.2025.14.07

Apoptozole Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer

Authors

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

DOI:

https://doi.org/10.30683/1929-2279.2025.14.07

Keywords:

Lung cancer, Multidrug Resistance, ABCG2, Apoptozole, Chemotherapy Sensitivity, Molecular Docking

Abstract

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.

References

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. DOI: https://doi.org/10.1016/j.drup.2022.100905

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. DOI: https://doi.org/10.1016/j.drup.2016.05.001

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. DOI: https://doi.org/10.1097/CAD.0b013e328354a196

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. DOI: https://doi.org/10.1002/jcb.24787

Doyle L, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22: 7340-7358. DOI: https://doi.org/10.1038/sj.onc.1206938

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. DOI: https://doi.org/10.1023/A:1012879205914

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. DOI: https://doi.org/10.1016/j.phrs.2017.01.035

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. DOI: https://doi.org/10.1016/j.phrs.2019.104297

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. DOI: https://doi.org/10.3389/fonc.2021.680663

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. DOI: https://doi.org/10.3389/fcell.2020.601400

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. DOI: https://doi.org/10.3389/fphar.2016.00518

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. DOI: https://doi.org/10.3390/biomedicines11113103

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. DOI: https://doi.org/10.2174/1574892817666220112100036

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. DOI: https://doi.org/10.3389/fonc.2020.00228

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. DOI: https://doi.org/10.3389/fphar.2021.620874

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. DOI: https://doi.org/10.3390/cancers13184675

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. DOI: https://doi.org/10.3389/fcell.2020.607275

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. DOI: https://doi.org/10.1016/j.canlet.2016.11.011

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. DOI: https://doi.org/10.1002/anie.200802801

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. DOI: https://doi.org/10.1021/ja206762p

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. DOI: https://doi.org/10.1016/j.chembiol.2015.02.004

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. DOI: https://doi.org/10.1039/C4MB00695J

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. DOI: https://doi.org/10.1038/srep17642

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. DOI: https://doi.org/10.1016/j.bbadis.2024.167137

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. DOI: https://doi.org/10.1016/j.biomaterials.2023.122354

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. DOI: https://doi.org/10.1039/D1NR03161A