Wednesday, May 5, 2021

Cilostazol eliminates radiation-resistant glioblastoma by re-evoking big conductance calcium-activated potassium channel activity

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Am J Cancer Res. 2021 Apr 15;11(4):1148-1169. eCollection 2021.

ABSTRACT

In spite of radio- and chemotherapy, glioblastoma (GBM) develops therapeutic resistance leading to recurrence and poor prognosis. Therefore, understanding the underlying mechanisms of resistance is important to improve the treatment of GBM. To this end, we developed a radiation-resistant cell model by exposure to consecutive periods of irradiation. Simultaneously, single high-dose irradiation was introduced to determine "when" GBM developed consecutive irradiation-induced resistance (CIIR). We found that CIIR promoted TGF-β secretion, activated pro-survival Akt, and downregulated p21 in a p53-independent manner. Furthermore, CIIR upregulated multidrug-resistant proteins, resulting in temozolomide resistance. CIIR GBM also enhanced cell mobility and accelerated cell proliferation. The big-conductance calcium-activated potassium channel (BK channel) is highly expre ssed and activated in GBM. However, CIIR diminishes BK channel activity in an expression-independent manner. Cilostazol is a phosphodiesterase-3 inhibitor for the treatment of intermittent claudication and was able to reverse CIIR-induced BK channel inactivation. Paxilline, a BK channel blocker, promoted cell migration and proliferation in parental GBM cells. In contrast, Cilostazol inhibited CIIR-induced cell motility, proliferation, and the ability to form tumor spheres. Moreover, we established a radiation-resistant GBM in vivo model by intracranially injecting CIIR GBM cells into the brains of NOD/SCID mice. We found that Cilostazol delayed tumor in vivo growth and prolonged survival. As such, inactivation of the BK channel assists GBM in developing radiation resistance. Accordingly, restoring BK channel activity may be an effective strategy to improve therapeutic efficacy, and cilostazol could be repurposed to treat GBM.

PMID:33948351 | PMC:PMC8085866

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