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

Mol Cancer Ther. 2018 Dec;17(12):2598-2609. doi: 10.1158/1535-7163.MCT-18-0533. Epub 2018 Sep 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Brain Neoplasms / pathology*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Female
  • Glioblastoma / pathology*
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Temozolomide / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carbonic Anhydrase Inhibitors
  • Doxorubicin
  • Carbonic Anhydrases
  • carbonic anhydrase XII
  • Temozolomide