title: An oxygen-chelate complex, palladium bis-acetylacetonate, induces apoptosis in H460 cells via endoplasmic reticulum stress pathway rather than interacting with DNA.
abstract: Current precious-metal-containing anticancer agents are mostly chelated with N-containing ligands and function by interacting with DNA. In the present study, Pd(acac)2, a Pd(II) complex containing four O-donor ligands, has been evaluated as an active anticancer agent. Pd(acac)2 showed no interaction with N-ligand-containing DNA and the S-ligand-containing DMSO, probably because of the two six-member chelate rings that limit the release of the central Pd nuclei to bind to other ligands. Importantly, we found that Pd(acac)2 exhibited better growth inhibitory effects than cisplatin in several cancer cells. Treatment with Pd(acac)2 significantly induced apoptosis in H460 cells. Mechanistically, Pd(acac)2 induced the activation of a series of key components in ER stress-mediated apoptotic pathway, followed by caspase cleavage and activation, while cisplatin showed no similar effects. CHOP knockdown by specific siRNA significantly attenuated Pd(acac)2-induced cell apoptosis. Finally, Pd(acac)2 significantly inhibits H460 cell growth in xenograft mouse models. Taken together, these mechanistic insights on Pd(acac)2 provide us with a novel mechanism and strategy for the development of precious-metal-based anticancer drugs.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, 325035, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Yuepiao
authors.initials: Y
authors.lastname: Cai
authors.forename: Shanmei
authors.initials: S
authors.lastname: Xu
authors.forename: Bixia
authors.initials: B
authors.lastname: Weng
authors.forename: Kesong
authors.initials: K
authors.lastname: Peng
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wei
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010165:Palladium / Q000494:pharmacology / Q000627:therapeutic use; D010422:Pentanones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006885:Hydroxybutyrates; D009942:Organometallic Compounds; D010422:Pentanones; C049529:acetyl acetonate; D010165:Palladium; D002945:Cisplatin