Highly cytotoxic gold()-phosphane dithiocarbamate complexes trigger an ER stress-dependent immune response in ovarian cancer cells

• Published in: Dalton transactions : an international journal of inorganic chemistry 2020-06, Vol.49 (22), p.7355-7363
• Main Authors: Le, Hai Van, Babak, Maria V, Ehsan, Muhammad Ali, Altaf, Muhammad, Reichert, Lisa, Gushchin, Artem L, Ang, Wee Han, Isab, Anvarhusein A
• Format: Article
• Language: English
• Subjects: Activation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell cycle; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Chloroform; Crystallography; Cytotoxicity; Drug Screening Assays, Antitumor; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - immunology; Female; Humans; Immune system; Infrared spectroscopy; Molecular Structure; NMR; Nuclear magnetic resonance; Organogold Compounds - chemical synthesis; Organogold Compounds - chemistry; Organogold Compounds - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; Oxidative Stress - drug effects; Phosphines - chemistry; Phosphines - pharmacology; Platinum; Survival; Thiocarbamates - chemistry; Thiocarbamates - pharmacology; Toxicity; Tumor Cells, Cultured
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/d0dt01411g

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses. We hypothesized that Au complexes that induce severe ER stress might counteract pro-survival cellular attempts leading to the ER stress-mediated apoptosis and reduced platinum resistance. In this work, we prepared a series of highly cytotoxic Au I -dialkyldithiocarbamate complexes and investigated their anticancer potential in ovarian cancer cells. Complexes demonstrated surprisingly low stability in chloroform, resulting in the formation of an Au chain polymer, which also displayed excellent cytotoxicity. Lead complex 2 induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G 2 /M phase. Importantly, 2 caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response. Highly cytotoxic Au I -dithiocarbamate complexes were designed to induce severe integrative stress in ovarian cancer cells, leading to the surface exposure of calreticulin, which is a first step in the activation of immune system.