title: A novel temozolomide analog, NEO212, with enhanced activity against MGMT-positive melanoma in vitro and in vivo.
abstract: The alkylating agent temozolomide (TMZ) represents an important component of current melanoma therapy, but overexpression of O6-methyl-guanine DNA methyltransferase (MGMT) in tumor cells confers resistance to TMZ and impairs therapeutic outcome. We investigated a novel perillyl alcohol (POH)-conjugated analog of TMZ, NEO212, for its ability to exert anticancer activity against MGMT-positive melanoma cells. Human melanoma cells with variable MGMT expression levels were treated with NEO212, TMZ, or perillyl alcohol in vitro and in vivo, and markers of DNA damage and apoptosis, and tumor cell growth were investigated. NEO212 displayed substantially greater anticancer activity than any of the other treatments. It reduced colony formation of MGMT-positive cells up to eight times more effectively than TMZ, and much more potently induced DNA damage and cell death. In a nude mouse tumor model, NEO212 showed significant activity against MGMT-positive melanoma, whereas TMZ, or a mix of TMZ plus POH, was ineffective. At the same time, NEO212 was well tolerated. NEO212 may have potential as a more effective therapy for advanced melanoma, and should become particularly suitable for the treatment of patients with MGMT-positive tumors.
authors.affiliation: Department of Neurosurgery, University of Southern California, Los Angeles, CA, United States. Electronic address: tcchen@usc.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, University of Southern California, Los Angeles, CA, United States.
authors.forename: Hee-Yeon
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Department of Neurosurgery, University of Southern California, Los Angeles, CA, United States.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, CA, United States.
authors.forename: Niyati
authors.initials: N
authors.lastname: Jhaveri
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, CA, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosenstein-Sisson
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, CA, United States.
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, United States. Electronic address: schontha@usc.edu.
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; C000596794:NEO212; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
keywords: Chemoresistance; MGMT; O6-methylguanine-DNA methyltransferase; Perillyl alcohol