Implications in progression of pediatric glioblastomas after inhibition of carbonic anhydrases 9 and 12 under hypoxic condition

Abstract

Glioblastoma ( GB ) represents 7-9 % of pediatric CNS tumors and, despite the biomedical and technological advances, the survival of these patients is two years. This tumor exhibits complex genetic changes that result in genomic instability and high cellular heterogeneity. This condition comes from the relentless malignant progression, such as invasion and spread through the brain, recurrence and resistance to traditional treatments of radio- and chemotherapy. Accordingly, cancer cells undergo a series of genetic changes that increase cell survival and allow to adapt to hypoxic conditions, promoting the activation of HIF - 1± transcriptional complex. HIF- 1± controls the expression of target genes such as those encoding the carbonic anhydrases ( CAs). The isoforms related CAs 9 and 12 membrane are overexpressed in several types of tumors, to promote tumor acidification of the environment and are described in the literature as involved in cancer progression. Indisulam, a waterproof membrane sulfonamide, is a new drug for the treatment of cancer, with potent inhibition of these enzymes. Considering these aspects, our hypothesis is that selective inhibition of CAs by Indisulam in pediatric cell lines, should promote reduced ability to promote proliferation and increased apoptosis. If our hypothesis is confirmed, CAs 9 and 12, besides being interesting tool to study the physiological, pathological and molecular effect of these CAs in GB, may represent an important therapeutic target. Thus, this project aims to assess the effects of treatment of pediatric GB cell lines with Indisulam through in vitro functional assays.