Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma

Prashant Mujumdar; Joanna Kopecka; Silvia Bua; Claudiu T Supuran; Chiara Riganti; Sally-Ann Poulsen

doi:10.1021/acs.jmedchem.9b00282

Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma

J Med Chem. 2019 Apr 25;62(8):4174-4192. doi: 10.1021/acs.jmedchem.9b00282. Epub 2019 Apr 10.

Authors

Prashant Mujumdar¹, Joanna Kopecka², Silvia Bua³, Claudiu T Supuran³, Chiara Riganti², Sally-Ann Poulsen¹

Affiliations

¹ Griffith Institute for Drug Discovery , Griffith University , Don Young Road , Nathan, Brisbane , Queensland 4111 , Australia.
² Department of Oncology , University of Torino , Via Santena 5/bis , 10126 Torino , Italy.
³ NEUROFARBA Department, Sezione di Scienze Farmaceutiche , Università degli Studi di Firenze , Via Ugo Schiff 6 , 50019 Sesto Fiorentino, Florence , Italy.

PMID: 30925064
DOI: 10.1021/acs.jmedchem.9b00282

Abstract

The natural product primary sulfonamide, psammaplin C (1), when used in combination with clinically used chemotherapeutic drugs, including temozolomide, reverses multidrug resistance and increases survival in glioblastoma, a highly aggressive primary brain tumor. We showed previously that the mechanism of action of 1 is novel, acting to indirectly interfere with P-glycoprotein drug efflux activity as a consequence of carbonic anhydrase XII (CA XII) inhibition. To build structure-activity relationships, 45 derivatives of 1 were designed, synthesized, and evaluated against a panel of CA isoforms. Compound 55 was identified as a potent inhibitor of CA XII ( K_i = 0.56 nM) and was investigated in vitro and in vivo using samples from glioblastoma patients. The results strengthen the possibility that co-therapy of temozolomide with a CA XII inhibitor may more effectively treat glioblastoma by suppressing an important temozolomide resistance mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Brain Neoplasms / drug therapy
Brain Neoplasms / pathology
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrase Inhibitors / therapeutic use
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Cell Survival / drug effects
Drug Design
Drug Resistance, Neoplasm / drug effects*
Female
Glioblastoma / drug therapy
Glioblastoma / pathology
Humans
Mice
Mice, Nude
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Structure-Activity Relationship
Temozolomide / therapeutic use
Transplantation, Heterologous
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Protein Isoforms
Carbonic Anhydrases
carbonic anhydrase XII
Temozolomide