title: New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status.
abstract: We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.
authors.affiliation: Center of Excellence in Nanotechnology (CENT), King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Altaf
authors.affiliation: Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Monim-Ul-Mehboob
authors.affiliation: Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Abdel-Nasser
authors.initials: AN
authors.lastname: Kawde
authors.affiliation: Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, PN, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Corona
authors.affiliation: Center for Technological Transfer, Edmund Mach Foundation, Trento, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Larcher
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, Texas, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, PN, Italy.
authors.forename: Naike
authors.initials: N
authors.lastname: Casagrande
authors.affiliation: Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, PN, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Celegato
authors.affiliation: Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, PN, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Borghese
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, Texas, USA.
authors.forename: Zahid H
authors.initials: ZH
authors.lastname: Siddik
authors.affiliation: Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, PN, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Aldinucci
authors.affiliation: Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Anvarhusein A
authors.initials: AA
authors.lastname: Isab
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013859:Thiocarbamates / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D050607:Organogold Compounds; D011725:Pyridines; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D013859:Thiocarbamates; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D000111:Acetylcysteine
keywords: bipyridine; cisplatin resistance; gold(III) complexes; p53; reactive oxygen species