Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

JCI Insight. 2017 Dec 21;2(24):e92928. doi: 10.1172/jci.insight.92928.


Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.

Keywords: Brain cancer; Drug therapy; Neuroscience; Oncology; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / prevention & control*
  • Cell Proliferation / drug effects
  • DNA Damage
  • DNA, Neoplasm / genetics
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / prevention & control*
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology
  • Temozolomide / administration & dosage
  • Temozolomide / pharmacology
  • Xenograft Model Antitumor Assays


  • DNA, Neoplasm
  • Phenylurea Compounds
  • SLC-0111
  • Sulfonamides
  • Temozolomide