title: 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.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavavam
authors.forename: Ying
authors.initials: Y
authors.lastname: Chao
authors.forename: Ila Sri
authors.initials: IS
authors.lastname: Bharati
authors.forename: Valentina
authors.initials: V
authors.lastname: Fogal
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.forename: Xiuli
authors.initials: X
authors.lastname: Cong
authors.forename: Natsuko
authors.initials: N
authors.lastname: Nomura
authors.forename: Matt
authors.initials: M
authors.lastname: Gallagher
authors.forename: Taher
authors.initials: T
authors.lastname: Abbasi
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.forename: Milan
authors.initials: M
authors.lastname: Makale
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA. skesari@ucsd.edu.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D017277:Drug Approval; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018874:Spheroids, Cellular / Q000473:pathology; D014481:United States; D014486:United States Food and Drug Administration; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011804:Quinolines; D000077146:Irinotecan; C108475:pitavastatin; D002166:Camptothecin