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Open Access Highly Accessed Research

Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs

Pengfei Jiang1, Rajesh Mukthavavam1, Ying Chao1, Ila Sri Bharati1, Valentina Fogal1, Sandra Pastorino1, Xiuli Cong3, Natsuko Nomura1, Matt Gallagher1, Taher Abbasi4, Shireen Vali4, Sandeep C Pingle1, Milan Makale1 and Santosh Kesari123*

Author Affiliations

1 Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA

2 Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA

3 Moores Cancer Center, UC San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA

4 CellWorks Inc., Irvine, CA USA

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Journal of Translational Medicine 2014, 12:13  doi:10.1186/1479-5876-12-13

Published: 17 January 2014

Abstract

Background

Glioblastoma (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.

Methods

Screens 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.

Results

Our data identifies a novel combination from among FDA-approved drugs. In addition, this combination is safer and well tolerated compared to single agent irinotecan.

Conclusions

Our 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.

Keywords:
Glioblastoma; Drug screening; Patient-derived glioblastoma cell lines; Rational combination