title: Characterization of a novel anti-cancer compound for astrocytomas.
abstract: The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.
authors.affiliation: Department of Neurosurgery, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Sang Y
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Becky
authors.initials: B
authors.lastname: Slagle-Webb
authors.affiliation: Department of Neurosurgery, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Elias
authors.initials: E
authors.lastname: Rizk
authors.affiliation: Department of Neurosurgery, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Akshal
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Radiology, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Patti A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Shen-Shu
authors.initials: SS
authors.lastname: Sung
authors.affiliation: Department of Neurosurgery, Pennsylvania State University College of Medicine, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001254:Astrocytoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D023382:Toxicity Tests, Acute; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D004250:DNA Topoisomerases, Type II; D045643:DNA Repair Enzymes; D000077204:Temozolomide