Low Concentration of Salinomycin Prevents Regrowth and Partially Depletes Human Glioma Cells Surviving High Concentrations of Alkylating Agents

Zahid   M.   Delwar; Avramidis      Dimitrios; Åke      Siden; Mabel      Cruz; Kajsa      Paulsson; Juan   Sebastian   Yakisich

Abstract

Glioblastoma is the most common primary brain tumor and one of the most devastating cancers. High-grade glioma patients’ prognoses are very poor, usually with a median survival of less than one year. Maximal neurosurgical resection followed by external adjuvant radiation therapy and chemotherapy is the conventional treatment for newly diagnosed high-grade glioma. Resistance to cytotoxic agents remains the greatest barrier to the successful treatment of human cancer. The alkylating agents temozolomide (TMZ), carmustine (BCNU), and lomustine (CCNU), which readily cross the blood-brain barrier, are the major chemotherapeutic candidates in glioma treatment, but many patients do not benefit from these drugs due to inherent or acquired resistance. We recently developed a two-phase treatment (2PT) aimed at eliminating drug resistant glioma cells by a second-phase treatment with a low concentration of salinomycin. In this study, we evaluated 1) the effect of prolonged exposure of clinically useful TMZ, BCNU, and CCNU on glioma cells; and 2) the fate of surviving cells as well as their sensitivity to a low concentration of salinomycin. We found that prolonged treatment with TMZ, BCNU, and CCNU induces a senescent-like state in the resistant cells, and that they then can be partially eliminated with a second-phase treatment of a low concentration of salinomycin.

Keywords: Glioma, brain tumors, alkylating agents, temozolomide, BCNU, CCNU, salinomycin, senescence, relapse.