title: A novel carbazole derivative, MHY407, sensitizes cancer cells to doxorubicin-, etoposide-, and radiation treatment via DNA damage.
abstract: In this study, we synthesized a novel carbazole derivative, MHY407, as a sensitizer of cancer cells to increase DNA damage. We then evaluated the anticancer effects of MHY407 and identified the molecular mechanism for the sensitization of breast cancer cell lines. MHY407 significantly increased DNA damage as determined by DNA breakage, levels of damage-responsive proteins, and DNA foci. In addition, MHY407 increased p21 and decreased cyclin D1 protein levels. MHY407 also involved increased cell cycle arrest at the S phase. Furthermore, in doxorubicin and etoposide-treated breast cancer cells, co-treatment with MHY407 reduced cell viability and increased apoptosis. Co-treatment of MHY407 with doxorubicin or etoposide increased DNA damage-related proteins and foci formation, suggesting that increased DNA damage by MHY407 plays an important role in the sensitization. In addition, MHY407 also sensitized the cancer cells to DNA damaging radiation treatment. These results may contribute to the development of MHY407-based treatments for cancer patients receiving DNA-damage therapy.
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea. yoons@ncc.re.kr
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
authors.forename: Ju-Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Ahn
authors.forename: Gayoung
authors.initials: G
authors.lastname: Choi
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Zunhua
authors.initials: Z
authors.lastname: Yang
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013997:Time Factors
chemical_list: C580813:9-methyl-2-(oxiran-2-ylmethoxy)-9H-carbazole; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D002227:Carbazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004852:Epoxy Compounds; D011838:Radiation-Sensitizing Agents; D019938:Cyclin D1; D005047:Etoposide; D004317:Doxorubicin