Journal article
Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo
JCI insight, Vol.2(24), e92928
12/21/2017
DOI: 10.1172/jci.insight.92928
PMCID: PMC5752277
PMID: 29263302
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.
Details
- Title: Subtitle
- Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo
- Creators
- Nathaniel H Boyd - University of Alabama at BirminghamKiera Walker - University of Alabama at BirminghamJoshua Fried - Southern Research InstituteJames R Hackney - University of Alabama at BirminghamPaul C McDonald - BC Cancer Research CentreGloria A Benavides - University of Alabama at BirminghamRaffaella Spina - Case Western Reserve UniversityAlessandra Audia - The University of Texas MD Anderson Cancer CenterSarah E Scott - University of Alabama at BirminghamCatherine J Landis - Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USAAnh Nhat Tran - University of Alabama at BirminghamMark O Bevensee - University of Alabama at BirminghamCorinne Griguer - Department of Neurosurgery.Susan Nozell - Department of Radiation Oncology, and.G Yancey Gillespie - Department of Neurosurgery.Burt Nabors - Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USAKrishna P Bhat - The University of Texas MD Anderson Cancer CenterEli E Bar - Case Western Reserve UniversityVictor Darley-Usmar - University of Alabama at BirminghamBo Xu - Southern Research InstituteEmily Gordon - HudsonAlpha Institute for BiotechnologySara J Cooper - HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USAShoukat Dedhar - BC Cancer Research CentreAnita B Hjelmeland - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(24), e92928
- DOI
- 10.1172/jci.insight.92928
- PMID
- 29263302
- PMCID
- PMC5752277
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- S10 RR027822 / NCRR NIH HHS T32 NS048039 / NINDS NIH HHS R01 CA138517 / NCI NIH HHS F31 CA200085 / NCI NIH HHS R21 NS096531 / NINDS NIH HHS P30 NS047466 / NINDS NIH HHS R01 CA151522 / NCI NIH HHS P30 AI027767 / NIAID NIH HHS R01 CA187780 / NCI NIH HHS P20 CA151129 / NCI NIH HHS R21 NS100054 / NINDS NIH HHS R01 CA160821 / NCI NIH HHS P30 CA013148 / NCI NIH HHS
- Language
- English
- Date published
- 12/21/2017
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984312981002771
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