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

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.

• Authors: Pengfei Jiang, Rajesh Mukthavaram, Rajesh Mukthavavam, Ying Chao, Ila Sri Bharati, Valentina Fogal, Sandra Pastorino, Xiuli Cong, Natsuko Nomura, Matt Gallagher, Taher Abbasi, Shireen Vali, Sandeep C Pingle, Milan Makale, Santosh Kesari
• Journal: Journal of translational medicine (J Transl Med) Vol. 12 Pg. 13 (Jan 17 2014) ISSN: 1479-5876 [Electronic] England
• PMID: 24433351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Quinolines
• Irinotecan
• pitavastatin
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology, therapeutic use)
• Autophagy (drug effects)
• Blood-Brain Barrier (pathology)
• Brain Neoplasms (drug therapy, genetics, pathology)
• Camptothecin (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Approval
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Irinotecan
• Mice
• Mice, Nude
• Neoplastic Stem Cells (pathology)
• Quinolines (administration & dosage, pharmacology, therapeutic use)
• Spheroids, Cellular (pathology)
• United States
• United States Food and Drug Administration
• Xenograft Model Antitumor Assays