title: Double Blockade of Glioma Cell Proliferation and Migration by Temozolomide Conjugated with NPPB, a Chloride Channel Blocker.
abstract: Glioblastoma is the most common and aggressive primary malignant brain tumor. Temozolomide (TMZ), a chemotherapeutic agent combined with radiation therapy, is used as a standard treatment. The infiltrative nature of glioblastoma, however, interrupts effective treatment with TMZ and increases the tendency to relapse. Voltage-gated chloride channels have been identified as crucial regulators of glioma cell migration and invasion by mediating cell shape and volume change. Accordingly, chloride current inhibition by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), a chloride channel blocker, suppresses cell movement by diminishing the osmotic cell volume regulation. In this study, we developed a novel compound, TMZ conjugated with NPPB (TMZ-NPPB), as a potential anticancer drug. TMZ-NPPB blocked chloride currents in U373MG, a severely invasive human glioma cell line, and suppressed migration and invasion of U373MG cells. Moreover, TMZ-NPPB exhibited DNA modification activity similar to that of TMZ, and surprisingly showed remarkably enhanced cytotoxicity relative to TMZ by inducing apoptotic cell death via DNA damage. These findings indicate that TMZ-NPPB has a dual function in blocking both proliferation and migration of human glioma cells, thereby suggesting its potential to overcome challenges in current glioblastoma therapy.
authors.affiliation: Department of Biological Chemistry, Korea University of Science and Technology , Daejeon 34113, Republic of Korea.
authors.forename: Miri
authors.initials: M
authors.lastname: Park
authors.affiliation: Materials and Life Science Research Division, Korea Institute of Science and Technology , Seoul 02792, Republic of Korea.
authors.forename: Chiman
authors.initials: C
authors.lastname: Song
authors.affiliation: Materials and Life Science Research Division, Korea Institute of Science and Technology , Seoul 02792, Republic of Korea.
authors.forename: Hojong
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Biological Chemistry, Korea University of Science and Technology , Daejeon 34113, Republic of Korea.|Materials and Life Science Research Division, Korea Institute of Science and Technology , Seoul 02792, Republic of Korea.
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D020552:Comet Assay; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D005910:Glioma / Q000473:pathology*; D006801:Humans; D009579:Nitrobenzoates / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D018118:Chloride Channels; D009579:Nitrobenzoates; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D003606:Dacarbazine; D000077204:Temozolomide
keywords: NPPB; Temozolomide; chloride channel blocker; glioblastoma; migration; proliferation; voltage-gated chloride channel