Abstract
Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice. Recently, experimental evidence revealed the anti-proliferative activity of chlorpromazine against colon and brain tumors. Here, we used chemoresistant patient-derived glioma stem cells and chemoresistant human glioma cell lines to investigate the effects of chlorpromazine against chemoresistant glioma. Chlorpromazine selectively and significantly inhibited proliferation in chemoresistant glioma cells and glioma stem cells. Mechanistically, chlorpromazine inhibited cytochrome c oxidase (CcO, complex IV) activity from chemoresistant but not chemosensitive cells, without affecting other mitochondrial complexes. Notably, our previous studies revealed that the switch to chemoresistance in glioma cells is accompanied by a switch from the expression of CcO subunit 4 isoform 2 (COX4-2) to COX4-1. In this study, chlorpromazine induced cell cycle arrest selectively in glioma cells expressing COX4-1, and computer-simulated docking studies indicated that chlorpromazine binds more tightly to CcO expressing COX4-1 than to CcO expressing COX4-2. In orthotopic mouse brain tumor models, chlorpromazine treatment significantly increased the median overall survival of mice harboring chemoresistant tumors. These data indicate that chlorpromazine selectively inhibits the growth and proliferation of chemoresistant glioma cells expressing COX4-1. The feasibility of repositioning chlorpromazine for selectively treating chemoresistant glioma tumors should be further explored.
Highlights
Temozolomide (TMZ), an alkylating agent that has shown significant initial benefit in the treatment of high-grade gliomas, especially when combined with radiotherapy, is commonly used in the adjunctive treatment of gliomas
Because CPZ blocked cell proliferation in chemoresistant glioma cells, we investigated whether CPZ blocks cell proliferation in the proportion of TMZ-resistant cells that have glioma stem cells (GSCs) properties
Because we previously demonstrated that the expression of COX4-1, rather than COX4-2, is in part responsible for the expansion of GSCs [11], the cells implicated in tumor recurrence and resistance to therapy in patients with glioblastoma, we tested the effect of CPZ in U251 glioma cells transfected with FLAG-epitope-tagged COX4-1 (U251-TgCOX4-1) or FLAG-epitope-tagged COX4-2 (U251-TgCOX4-2)
Summary
Temozolomide (TMZ), an alkylating agent that has shown significant initial benefit in the treatment of high-grade gliomas, especially when combined with radiotherapy, is commonly used in the adjunctive treatment of gliomas. TMZ chemotherapy eventually becomes impaired by the development of chemoresistance. This phenomenon presents the most challenging barrier in the successful treatment of cancer and is the principal reason for chemotherapy failure and one of the main reasons underlying the failure to demonstrate a sustainable beneficial clinical outcome for patients with glioblastoma (GBM) [1, 2]. CSCs driven by mitochondrial oxidative phosphorylation (OxPhos) have been identified in lung cancer [8, 9], glioma [10,11,12], pancreatic cancer [13], and leukemia stem cells [14]. Regardless of the primary metabolic phenotype, mitochondrial function appears to be critical for CSC functionality, and elimination of highly chemoresistant CSCs via inhibition of mitochondrial function may prevent relapse from disease and improve patients’ long-term outcome [4]
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