Anti-breast cancer action of carbonic anhydrase IX inhibitor 4-[4-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-benzylidene-hydrazinocarbonyl]-benzenesulfonamide (BSM-0004): in vitro and in vivo studies

Chandra Bhushan Mishra; Raj Kumar Mongre; Amresh Prakash; Raok Jeon; Claudiu T Supuran; Myeong-Sok Lee

doi:10.1080/14756366.2021.1909580

Anti-breast cancer action of carbonic anhydrase IX inhibitor 4-[4-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-benzylidene-hydrazinocarbonyl]-benzenesulfonamide (BSM-0004): in vitro and in vivo studies

J Enzyme Inhib Med Chem. 2021 Dec;36(1):954-963. doi: 10.1080/14756366.2021.1909580.

Authors

Chandra Bhushan Mishra¹, Raj Kumar Mongre², Amresh Prakash³, Raok Jeon¹, Claudiu T Supuran⁴, Myeong-Sok Lee²

Affiliations

¹ College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
² Department of Biosystem, Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Sookmyung Women's University, Seoul, Republic of Korea.
³ Amity Institute of Integrative Sciences and Health, Amity University, Gurgaon, India.
⁴ Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universitàdegli Studi di Firenze, Florence, Italy.

Abstract

Anti-breast cancer action of novel human carbonic anhydrase IX (hCA IX) inhibitor BSM-0004 has been investigated using in vitro and in vivo models of breast cancer. BSM-0004 was found to be a potent and selective hCA IX inhibitor with a Ki value of 96 nM. In vitro anticancer effect of BSM-0004 was analysed against MCF 7 and MDA-MA-231 cells, BSM-0004 exerted an effective cytotoxic effect under normoxic and hypoxic conditions, inducing apoptosis in MCF 7 cells. Additionally, this compound significantly regulates the expression of crucial biomarkers associated with apoptosis. The investigation was extended to confirm the efficacy of this hCA IX inhibitor against in vivo model of breast cancer. The results specified that the treatment of BSM-0004 displayed an effective in vivo anticancer effect, reducing tumour growth in a xenograft cancer model. Hence, our investigation delivers an effective anti-breast cancer agent that engenders the anticancer effect by inhibiting hCA IX.

Keywords: Human carbonic anhydrase IX; breast cancer; cancer therapy; cytotoxicity; inhibition constant.

MeSH terms

Animals
Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Nude
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
CA9 protein, human
Carbonic Anhydrase IX

Grants and funding

This work was supported by a grant from the National Research Foundation of Korea (NRF) Republic of Korea Grant Nos. (MSIP)NRF-2020R1A2C1102100 and NRF-2016R1A5A1011974. This work was also funded by National Research Foundation of Korea (NRF) Grant Nos. 2019H1D3A2A02102142 and 2019R1F1A1057386 supported by the Korean Government (MSIP).