Abstract
BackgroundGlioblastoma (GBM) is a therapeutic challenge, associated with high mortality. More effective GBM therapeutic options are urgently needed. Hence, we screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM.MethodsScreens using human GBM cell lines revealed 22 drugs with potent anti-GBM activity, including serotonergic blockers, cholesterol-lowering agents (statins), antineoplastics, anti-infective, anti-inflammatories, and hormonal modulators. We tested the 8 most potent drugs using patient-derived GBM cancer stem cell-like lines. Notably, the statins were active in vitro; they inhibited GBM cell proliferation and induced cellular autophagy. Moreover, the statins enhanced, by 40-70 fold, the pro-apoptotic activity of irinotecan, a topoisomerase 1 inhibitor currently used to treat a variety of cancers including GBM. Our data suggest that the mechanism of action of statins was prevention of multi-drug resistance protein MDR-1 glycosylation. This drug combination was synergistic in inhibiting tumor growth in vivo. Compared to animals treated with high dose irinotecan, the drug combination showed significantly less toxicity.ResultsOur data identifies a novel combination from among FDA-approved drugs. In addition, this combination is safer and well tolerated compared to single agent irinotecan.ConclusionsOur study newly identifies several FDA-approved compounds that may potentially be useful in GBM treatment. Our findings provide the basis for the rational combination of statins and topoisomerase inhibitors in GBM.
Highlights
Novel therapeutic options are sorely needed to target glioblastoma (GBM), a notoriously treatment-resistant brain cancer
We found that the statin, pitavastatin, effectively induced cellular autophagy and suppressed tumor cell MDR-1 protein, to impressively enhance the potency of irinotecan, a topoisomerase 1 inhibitor used in cancer treatment [19,20,21]
Homoharringtonine and cerivastatin reduced survival to 10% percent or less, while 9 compounds reduced survival to less than 25%, 6 drugs reduced survival to less than 35%, and the remainder was associated with a survival of 35-50%
Summary
Novel therapeutic options are sorely needed to target glioblastoma (GBM), a notoriously treatment-resistant brain cancer. The standard therapies are inadequate, and their toxicities lead to severe life-long morbidity in the small number of patients that survive [2]. Despite this grim prognosis, GBM is an our goals were to identify and characterize single and combination agents having anti-GBM activity that we can potentially introduce into clinical trials quickly. GBM is an our goals were to identify and characterize single and combination agents having anti-GBM activity that we can potentially introduce into clinical trials quickly To this end, using GBM cell lines and patientderived GBM cell cultures, we screened a 446-compound NIH Clinical Collection (NCC) library comprising FDAapproved drugs. We screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM
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