title: Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo.
abstract: Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosyl)ation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP-ribose) polymerase (PARP) inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL-positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. yasukawa-masaaki@tsurumi-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. fujihara-h@tsurumi-u.ac.jp.|Department of Oral Hygiene, Tsurumi Junior College, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. fujihara-h@tsurumi-u.ac.jp.
authors.forename: Hisako
authors.initials: H
authors.lastname: Fujihara
authors.affiliation: Division of Chemotherapy and Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. hisakuma@ncc.go.jp.|Department of Frontier Life Science, Graduate School of Biochemical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan. hisakuma@ncc.go.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. kawaguchi-k@tsurumi-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Division of Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, School of Dentistry, Iwate Medical University 19-1 Uchimaru, Morioka Iwate 020-8050, Japan. yamadah@iwate-med.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Pathology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. nakayama-r@tsurumi-u.ac.jp.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Nakayama
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. yamamoto-nanami@tsurumi-u.ac.jp.
authors.forename: Nanami
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. kishi-y@tsurumi-u.ac.jp.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kishi
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. hamada-y@tsurumi-u.ac.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Division of Chemotherapy and Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. mmasutan@ncc.go.jp.|Department of Frontier Life Science, Graduate School of Biochemical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan. mmasutan@ncc.go.jp.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy*; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D002945:Cisplatin; C531550:olaparib
keywords: PARP inhibitor; cisplatin; oral cancer; xenografted tumor