journal contribution
posted on 2023-04-03, 16:04 authored by Iris C. Salaroglio, Prashant Mujumdar, Laura Annovazzi, Joanna Kopecka, Marta Mellai, Davide Schiffer, Sally-Ann Poulsen, Chiara Riganti The file contains Supplementary Figure S1-S6: Figure S1 shows Pgp and CAXII expression in different culture conditions; Figure S2 shows the effects of compounds 1-5 on chemotherapeutic drugs cytotoxicity; Figure S3 shows the effects of compound 1 and temozolomide in Pgp KO clones; Figure S4 shows isobologram analysis; Figure S5 shows CAXII-KO clones; Figure S6 shows AC and NS tumor growth with different dosing of compound 1 and temozolomide.
Funding
Italian Association for Cancer Research
Italian Ministry of University and Research
Australian Research Council
Italian Institute for Security Service 2014-2017
History
ARTICLE ABSTRACT
The role of carbonic anhydrase XII (CAXII) in the chemoresistance of glioblastoma is unexplored. We found CAXII and P-glycoprotein (Pgp) coexpressed in neurospheres derived from 3 of 3 patients with different genetic backgrounds and low response to temozolomide (time to recurrence: 6–9 months). CAXII was necessary for the Pgp efflux of temozolomide and second-line chemotherapeutic drugs, determining chemoresistance in neurospheres. Psammaplin C, a potent inhibitor of CAXII, resensitized primary neurospheres to temozolomide by reducing temozolomide efflux via Pgp. 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, codosed 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.
