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

Academic Article

Abstract

  • 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.

    • Published In

  • JCI insight  Journal

    • Keywords

  • Brain cancer, Drug therapy, Neuroscience, Oncology, hypoxia, Animals, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Cell Proliferation, DNA Damage, DNA, Neoplasm, Glioblastoma, Humans, Hydrogen-Ion Concentration, Mice, Nude, Neoplastic Stem Cells, Phenylurea Compounds, Sulfonamides, Temozolomide, Xenograft Model Antitumor Assays

    • Digital Object Identifier (doi)

    Author List

  • Boyd NH; Walker K; Fried J; Hackney JR; McDonald PC; Benavides GA; Spina R; Audia A; Scott SE; Libby CJ

    • Volume

  • 2

    • Issue

  • 24