Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line

• Published in: CNS neuroscience & therapeutics Vol. 28; no. 9; pp. 1447 - 1457
• Main Authors: Drljača, Jovana, Popović, Aleksandra, Bulajić, Dragica, Stilinović, Nebojša, Vidičević Novaković, Sašenka, Sekulić, Slobodan, Milenković, Ivan, Ninković, Srđan, Ljubković, Marko, Čapo, Ivan
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-09-2022; John Wiley and Sons Inc
• Subjects: Antibodies; antineoplastic agent; Antitumor activity; Apoptosis; Benzodiazepines; Brain cancer; Cell cycle; Cell viability; Chemotherapy; Cytotoxicity; Diazepam; drug interactions; Electron transport chain; Epilepsy; G1 phase; Gene expression; Glioblastoma; Medical prognosis; Mental disorders; Mitochondria; Morphology; Neurological diseases; Original; Oxidative phosphorylation; Oxygen consumption; Patients; Phosphorylation; Radiation therapy; Respiration; Senescence; Temozolomide; Tumors; U87 glioblastoma; Variance analysis; Vomiting; Wound healing; U87 glioblastoma; drug interactions; antineoplastic agent; mitochondria; oxidative phosphorylation
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13889

Aims
Many patients with glioblastoma (GBM) suffer from comorbid neurological/psychiatric disorders and, therefore, are treated with psychopharmacological agents. Diazepam (DIA) is widely adopted to treat status epilepticus, alleviate anxiety, and inhibit chemotherapy‐associated delayed emesis in GBM patients. Even though temozolomide (TMZ) and DIA could be found as possible combination therapy in clinical practice, there are no reports of their combined effects in GBM. Hence, it may be of interest to investigate whether DIA enhances the antitumor efficacy of TMZ in GBM cells.
Methods
U87 human GBM was used to examine the effects of combined TMZ and DIA on cell viability, and the oxygen consumption within the cells, in order to evaluate mitochondrial bioenergetic response upon the treatment.
Results
The cooperative index showed the presence of antagonism between TMZ and DIA, which was confirmed on long‐term observation. Moreover, the level of apoptosis after the TMZ treatment was significantly decreased when administered with DIA (p < 0.001). Concomitant use of TMZ and DIA increased the basal cell respiration rate, the oxidative phosphorylation rate, and maximal capacity of mitochondrial electron transport chain, as well as the activities of complexes I and II, vs. TMZ alone (p < 0.001).
Conclusion
Comparing our results with data reported that DIA elicits cell cycle arrest in the G0/G1 phase and favors senescence reveals that DIA diminishes TMZ efficacy in concomitant use in the treatment of GBM. However, due to its great potency to hinder GBM proliferation and metabolism, it could be considered using DIA as maintenance therapy after TMZ cycles.
Temozolomide exerts its effects through the ability to methylate DNA, which leads to base mismatches and finally resulting in G2/M cell cycle arrest, and ultimately apoptosis. Given that diazepam triggers G0/G1 cell cycle arrest in glioblastoma cells, thus blocking the DNA replication, it diminishes the temozolomide efficacy in concomitant use and should not be administered together.