title: Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety.
abstract: By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research and Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors: Lei
authors: L
authors: Fang
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research and Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Minchang
authors: M
authors: Feng
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research and Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Feihong
authors: F
authors: Chen
authors: Department of Science and Technology, Jiangsu Open University, Nanjing 210036, China.
authors: Xia
authors: X
authors: Liu
authors: Department of Science and Technology, Jiangsu Open University, Nanjing 210036, China.
authors: Hong
authors: H
authors: Shen
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research and Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Jian
authors: J
authors: Zhao
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research and Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
authors: Shaohua
authors: S
authors: Gou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000494:pharmacology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D009944:Organoplatinum Compounds; D009828:Oleanolic Acid
keywords: Hepatoma carcinoma; Nitric oxide donor; Oleanolic acid; Platinum complex