title: Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells.
abstract: BACKGROUND
  Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients.
  
  
  METHODS
  We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl2 (L)] and [PdCl2 (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP-resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl2 (L)] and [PdCl2 (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo.
  
  
  RESULTS
  CDDP-resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP-resistant gastric cancer cells, [PdCl2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl2 (L)] induced DNA double-strand breaks.
  
  
  CONCLUSIONS
  These results indicate that [PdCl2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. hkataoka@med.nagoya-cu.ac.jp
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yano
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ohi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibahara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mizoshita
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019942:Genes, p16; D006001:Glycoconjugates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010165:Palladium / Q000494:pharmacology / Q000627:therapeutic use*; D010984:Platinum / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D015854:Up-Regulation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006001:Glycoconjugates; D010984:Platinum; D010165:Palladium; D002945:Cisplatin