Date of Award
2026
Document Type
Thesis
Degree Name
MS in Pharmaceutical Science
Department
Pharmaceutical Sciences
First Advisor
Vikas V Dukhande
Second Advisor
Sunil Kumar
Third Advisor
Shanzhi Wang
Abstract
Glioblastoma multiforme (GBM) is a grade 4 malignant primary brain tumor characterized by poor prognosis and a limited response to the current treatments. Temozolomide (TMZ) is the standard chemotherapeutic agent; resistance to TMZ and its reduced efficacy within the hypoxic GBM microenvironment continue to present major obstacles. In oxygen-poor conditions, GBM cells shift metabolism toward glycolysis and increase lactate production, a change driven by lactate dehydrogenase (LDH), which converts pyruvate to lactate and replenishes the cofactor required for glycolysis. Interestingly, LDH expression shows a negative correlation with GBM patient survival. Inhibiting LDH may therefore offer a way to target hypoxia-adapted GBM cells. Our study examined the effects of three LDH inhibitors on the viability, long-term survival, three-dimensional (3D) growth, and hypoxia-inducible factor-1α (HIF-1α) signaling in U87-MG and LN229 GBM cells under normoxic and hypoxic conditions. Human GBM cells were treated with stiripentol (STP), FX11, or GSK-2837808A, with TMZ as a comparison control. Oxygen conditions of 21%, 2.5%, and 1% O₂ were initially evaluated, and 1% O₂ was selected as the hypoxic condition for subsequent experiments. Cell viability was determined using the MTT assay, long-term survival using the clonogenic assay, and treatment efficacy using 3D spheroid models. Expression of LDHA and HIF-1α was measured by immunoblotting. In both cell lines, all three inhibitors reduced GBM cell viability in a concentration- and time-dependent manner. Hypoxia increased the sensitivity to LDH inhibition but not to TMZ treatment, an effect most apparent at 48 hours. All three inhibitors reduced colony formation in a concentration-dependent manner, and the effects were similar across the oxygen conditions. In 3D spheroid models, LDH inhibition limited spheroid growth, disrupted spheroid morphology, and increased dead-cell staining. Immunoblotting showed higher LDHA and HIF-1α expression under hypoxic conditions in LN229 cells at both time points, whereas the drug treatment response varied by treatment and time point. Together, these findings indicate hypoxia increases GBM cell sensitivity to LDH inhibition while reducing responsiveness to TMZ. Therefore, the role of hypoxia in GBM needs an in-depth understanding, and LDH as a therapeutic target for GBM merits further exploration.
Recommended Citation
Anumarlapudi, Sri Sai Susmitha, "ELUCIDATING THE ROLE OF HYPOXIA IN MODULATING THE EFFECT OF LDH INHIBITORS IN GLIOBLASTOMA CELLS" (2026). Theses and Dissertations. 1132.
https://scholar.stjohns.edu/theses_dissertations/1132