Indisulam Reduces Viability and Regulates Apoptotic Gene Expression in Pediatric High-Grade Glioma Cells

Abstract

Pediatric high-grade glioma (pHGG) is one of the most aggressive brain tumors. Treatment includes surgery, radiotherapy, chemotherapy, or combination therapy in children older than 3–5 years of age. These devastating tumors are influenced by the hypoxic microenvironment that coordinatively increases the expression of carbonic anhydrases (CA9 and CA12) that are involved in pH regulation, metabolism, cell invasion, and resistance to therapy. The synthetic sulphonamide Indisulam is a potent inhibitor of CAs. The aim of this study was to evaluate the effects of Indisulam on CA9 and CA12 enzymes in pHGG cell lines. Our results indicated that, under hypoxia, the gene and protein expression of CA9 and CA12 are increased in pHGG cells. The functional effects of Indisulam on cell proliferation, clonogenic capacity, and apoptosis were measured in vitro. CA9 and CA12 gene and protein expression were analyzed by RT-PCR and western blot. The treatment with Indisulam significantly reduced cell proliferation (dose-time-dependent) and clonogenic capacity (p < 0.05) and potentiated the effect of apoptosis (p < 0.01). Indisulam promoted an imbalance in the anti-apoptotic BCL2 and pro-apoptotic BAX protein expression. Our results demonstrate that Indisulam contributes to apoptosis via imbalance of apoptotic proteins (BAX/BCL2) and suggests a potential to overcome chemotherapy resistance caused by the regulation these proteins.

The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells

“…These findings are consistent with the results of previously published studies investigating compounds with similar structures. It is worth noting that indisulam, which belongs to the sulfonamide class, has anticancer activity through several mechanisms [ 27 , 28 , 29 ]. These include inhibition of carbonic anhydrase, affecting various cell cycle checkpoints, and inducing apoptosis by affecting apoptotic Bax/Bcl2 proteins.…”

“…These include inhibition of carbonic anhydrase, affecting various cell cycle checkpoints, and inducing apoptosis by affecting apoptotic Bax/Bcl2 proteins. It is currently in phase I/II clinical trials [ 27 , 28 , 29 ]. In addition, purine-based compounds continue to be an attractive scaffold for the development of new antitumor agents.…”