Carbonic Anhydrase XII Inhibitors Overcome P-Glycoprotein–Mediated Resistance to Temozolomide in Glioblastoma

The role of carbonic anhydrase XII (CAXII) in the chemoresistance of glioblastoma is unexplored. We found CAXII and P-glycoprotein co-expressed in neurospheres derived from 3/3 patients with different genetic backgrounds and low response to temozolomide (time to recurrence: 6-9 months). CAXII was necessary for the P-glycoprotein efflux of temozolomide and second-line chemotherapeutic drugs, determining chemoresistance in neurospheres. Psammaplin C, a potent inhibitor of CAXII, re-sensitized primary neurospheres to temozolomide by reducing temozolomide efflux via P-glycoprotein. This effect was independent of other known temozolomide resistance factors present in the patients. The overall survival in orthotopic patient-derived xenografts of temozolomide-resistant neurospheres, co-dosed with Psammaplin C and temozolomide, was significantly increased over temozolomide-treated (p<0.05) and untreated animals (p<0.02), without detectable signs of systemic toxicity. We propose that a CAXII inhibitor in combination with temozolomide may provide a new and effective approach to reverse chemoresistance in glioblastoma stem cells. This novel mechanism of action, via the interaction of CAXII and Pgp, ultimately blocks the efflux function of Pgp to improve glioblastoma patient outcomes.