Brecht, Karin, Riebel, Virginie, Couttet, Philippe, Paech, Franziska, Wolf, Armin, Chibout, Salah-Dine, Pognan, Francois, Krähenbühl, Stephan and Uteng, Marianne (2017) Mechanistic insights into selective killing of OXPHOS-dependent pancreatic cancer cells by arctigenin. Toxicology in vitro, 40. pp. 55-65. ISSN 08872333

Abstract

Arctigenin has previously been identified as a potential anti-tumor treatment for advanced pancreatic cancer. However, the mechanism of how arctigenin kills cancer cells is not fully understood. In the present work we studied arctigenin’s mechanism of toxicity in the human pancreatic cell line, Panc-1, with special emphasis on the mitochondria. A comparison of Panc-1 cells cultured in glucose versus galactose medium was applied, allowing assessments of effects in glycolytic versus oxidative phosphorylation (OXPHOS)-dependent Panc-1 cells. The response to treatment with arctigenin was compared to sorafenib for control purposes.

Arctigenin selectively killed OXPHOS-dependent Panc-1 cells mainly via apoptosis, aponecrosis and minimal necrosis, while it did not kill glycolytic Panc-1 cells. In both OXPHOS-dependent and glycolytic cells, arctigenin dissipated the mitochondrial membrane potential, which was demonstrated to be due to inhibition of the mitochondrial complexes II and IV. The selective killing of OXPHOS-dependent Panc-1 cells by arctigenin was, however, due to generation of additional ER stress, mitochondrial membrane permeabilization and caspase activation leading to apoptosis and aponecrosis. In conclusion, these results confirm that arctigenin is a mitochondrial toxicant and enlarge our knowledge about the mechanisms involved. Importantly, they provide a more comprehensive insight than currently available into how arctigenin selectively kills OXPHOS-dependent cells.

Item Type:	Article
Date Deposited:	01 Feb 2017 00:45
Last Modified:	01 Feb 2017 00:45
URI:	https://oak.novartis.com/id/eprint/29494