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 and Juan Sebastian Yakisich
Affiliation: Department of Clinical Neuroscience R54, Karolinska Institute, Karolinska University Hospital, Sweden, S-141 86, Stockholm, Sweden.
Keywords: Glioma, brain tumors, alkylating agents, temozolomide, BCNU, CCNU, salinomycin, senescence, relapse.
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.
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