TY - JOUR

T1 - Highly cytotoxic gold(i)-phosphane dithiocarbamate complexes trigger an ER stress-dependent immune response in ovarian cancer cells

AU - Le, Hai Van

AU - Babak, Maria V.

AU - Ehsan, Muhammad Ali

AU - Altaf, Muhammad

AU - Reichert, Lisa

AU - Gushchin, Artem L.

AU - Ang, Wee Han

AU - Isab, Anvarhusein A.

PY - 2020/6/14

Y1 - 2020/6/14

N2 - 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 AuI-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 complex2induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly,2caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response.

AB - 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 AuI-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 complex2induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly,2caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response.

UR - http://www.scopus.com/inward/record.url?scp=85086285658&partnerID=8YFLogxK

U2 - 10.1039/d0dt01411g

DO - 10.1039/d0dt01411g

M3 - Article

C2 - 32432621

AN - SCOPUS:85086285658

VL - 49

SP - 7355

EP - 7363

JO - Dalton Transactions

JF - Dalton Transactions

SN - 1477-9226

IS - 22

ER -