Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole

• Published in: Cancer chemotherapy and pharmacology Vol. 90; no. 4; pp. 345 - 356
• Main Authors: Karve, Aniruddha S., Desai, Janki M., Dave, Nimita, Wise-Draper, Trisha M., Gudelsky, Gary A., Phoenix, Timothy N., DasGupta, Biplab, Sengupta, Soma, Plas, David R., Desai, Pankaj B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2022; Springer Nature B.V
• Subjects: 17β-Estradiol; Alkylation; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis; Aromatase; Aromatase Inhibitors - pharmacology; Brain cancer; Brain Neoplasms - genetics; Cancer Research; Cell Line, Tumor; Cell viability; Cytotoxicity; Damage assessment; Deoxyribonucleic acid; Deprivation; DNA; DNA damage; Drug resistance; Drug Resistance, Neoplasm; Estradiol - pharmacology; Estrogens; Evaluation; Glioblastoma; Glioblastoma - metabolism; Glioblastoma cells; Humans; Inhibitors; Letrozole - pharmacology; Letrozole - therapeutic use; Medicine; Medicine & Public Health; Oncology; Original Article; Patients; Pharmacology/Toxicology; Potentiation; Sex hormones; Temozolomide; Temozolomide - pharmacology; Temozolomide - therapeutic use; Toxicity; Temozolomide; Drug-resistance; Synergism; Letrozole; Glioblastoma; Aromatase inhibitors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-022-04469-5

Purpose The DNA alkylating agent temozolomide (TMZ), is the first-line therapeutic for the treatment of glioblastoma (GBM). However, its use is confounded by the occurrence of drug resistance and debilitating adverse effects. Previously, we observed that letrozole (LTZ), an aromatase inhibitor, has potent activity against GBM in pre-clinical models. Here, we evaluated the effect of LTZ on TMZ activity against patient-derived GBM cells. Methods Employing patient-derived G76 (TMZ-sensitive), BT142 (TMZ-intermediately sensitive) and G43 and G75 (TMZ-resistant) GBM lines we assessed the influence of LTZ and TMZ on cell viability and neurosphere growth. Combination Index (CI) analysis was performed to gain quantitative insights of this interaction. We then assessed DNA damaging effects by conducting flow-cytometric analysis of ˠH2A.X formation and induction of apoptotic signaling pathways (caspase3/7 activity). The effects of adding estradiol on LTZ-induced cytotoxicity and DNA damage were also evaluated. Results Co-treatment with LTZ at a non-cytotoxic concentration (40 nM) reduced TMZ IC 50 by 8, 37, 240 and 640 folds in G76, BT-142, G43 and G75 cells, respectively. The interaction was deemed to be synergistic based on CI analysis. LTZ co-treatment also significantly increased DNA damaging effects of TMZ. Addition of estradiol abrogated these LTZ effects. Conclusions LTZ increases DNA damage and synergistically enhances TMZ activity in TMZ sensitive and TMZ-resistant GBM lines. These effects are abrogated by the addition of exogenous estradiol underscoring that the observed effects of LTZ may be mediated by estrogen deprivation. Our study provides a strong rationale for investigating the clinical potential of combining LTZ and TMZ for GBM therapy.