Editors' ChoiceCancer

Repurposing drugs for glioblastoma

Sci. Signal.  03 Nov 2015:
Vol. 8, Issue 401, pp. ec321
DOI: 10.1126/scisignal.aad7743

Long-term use of certain antidepressants has been associated with decreased incidence of gliomas, possibly through the induction of autophagy, the catabolic process of breaking down cellular components. In a transgenic mouse model of glioma, Shchors et al. found that the tricyclic antidepressant imipramine induced autophagy and impaired proliferation in glioma tumors and extended the life span of mice with low-grade, but not high-grade, tumors. This difference in low- versus high-grade tumor-bearing mice is consistent with the observation that prescribing imipramine after diagnosis lacks a survival benefit in glioma patients. Therefore, the authors screened for drugs that enhanced imipramine’s antiproliferative effects in cultured human glioma cell lines. Only one of those tested, the anticoagulant drug ticlopidine, enhanced the toxicity of imipramine in all cell lines tested, but ticlopidine inhibits the adenosine diphosphate receptor P2Y12, an abundant receptor on platelets. Glioma cells had increased abundance of P2Y12 compared with the amount in normal glial cells. Combining other tricyclic antidepressants with other P2Y12 inhibitors was also synergistically toxic to glioma cells in culture. Blocking P2Y12 maintains a high activity of adenylyl cyclase and subsequently high production of cyclic adenosine monophosphate (cAMP), which can alter the balance of AMP:ATP, thereby increasing autophagy. The combination of imipramine and ticlopidine increased the rate of autophagy, inferred from the detection of various autophagy proteins and structures in tumor cells in culture or in mice, above that induced by either drug alone. Pharmacologically inhibiting autophagy or knocking down key autophagy mediators impaired the cytotoxic synergy of the drug combination in tumor cells in culture or in mice. Treating transgenic or xenografted glioma-bearing mice with the combined therapy of imipramine and ticlopidine had a greater effect of increasing survival and suppressing tumor progression than either monotherapy, even in mice with late-stage tumors. The findings indicate that the toxic amount of autophagy triggered by the combination of tricyclic antidepressants and P2Y12 inhibitors may be therapeutically beneficial for glioma patients.

K. Shchors, A. Massaras, D. Hanahan, Dual targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal autophagy and therapeutic benefit. Cancer Cell 28, 456–471 (2015). [PubMed]