title: NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas.
abstract: Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O(6) methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O(6)-benzylguanine (O(6)BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomide-resistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.
authors.affiliation: Departments of Neurosurgery.
authors.forename: Hee-Yeon
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Departments of Neurosurgery.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Pathology, and.
authors.forename: Niyati
authors.initials: N
authors.lastname: Jhaveri
authors.affiliation: Pathology, and.
authors.forename: David Jungpa
authors.initials: DJ
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California.
authors.forename: Natasha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Pathology, and.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.affiliation: Molecular Microbiology and Immunology, Keck School of Medicine; and.
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
authors.affiliation: Departments of Neurosurgery, Pathology, and tcchen@med.usc.edu hofman@usc.edu.
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.affiliation: Departments of Neurosurgery, Pathology, and tcchen@med.usc.edu hofman@usc.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008819:Mice, Nude; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000596794:NEO212; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes