search for




 

Mechanisms of Growth Inhibition by Sulfasalazine and Erastin in Hepatocellular Carcinoma Cell Lines
Yakhak Hoeji 2019;63(3):152-159
Published online June 30, 2019
© 2019 The Pharmaceutical Society of Korea.

Do Hyung Kim, MD Abdullah, and Seung Jin Lee#

College of Pharmacy, Chungnam National University
Correspondence to: #Seung Jin Lee, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea Tel: +82-42-821-5940 E-mail: s.j.lee@cnu.ac.kr
Received April 9, 2019; Revised June 11, 2019; Accepted June 11, 2019.
Abstract
Aberrant gene expression in the cell death pathway is a hallmark of cancers. Sulfasalazine and erastin are representative inducers of ferroptosis, which is a form of regulated cell death caused by iron-mediated accumulation of lethal lipid peroxides. This study aimed to evaluate the vulnerability of hepatocellular carcinoma cells to ferroptotic inducers. Sulfasalazine and erastin decreased cell viability with an increase of membrane permeabilization in Huh7, Huh6, and HepG2 cells. 2-Mercaptoethanol, a reducing agent, prevented cell death induced by 500 µM sulfasalazine in all tested cell lines, whereas ferrostatin-1, a ferroptosis inhibitor, restored by 57.5, 45.8, and 21.9% in Huh7, Huh6, and HepG2 cells, respectively. The cell death induced by 3 µM erastin was reversed in the presence of ferrostatin-1, by 42.9, 45.3, and 29% in Huh7, Huh6, and HepG2 cells, respectively. Necrostatin-1, a RIPK1 inhibitor, restored sulfasalazine- or erastin-induced cell death to a similar extent as ferrostatin-1. Z-VAD-FMK, a pan-caspase inhibitor, and chloroquine, an autophagy inhibitor, failed to prevent sulfasalazine- or erastin-induced cell death. The increase of lipid peroxide by sulfasalazine was higher in Huh7 cells than in HepG2 cells, and was prevented by ferrostatin-1 and necrostatin-1 treatment of Huh7 cells. In contrast, sulfasalazine and erastin decreased the viability of PLC/PRF/5 cells by 60% without significant morphological changes, which was not affected by any inhibitor. Together, these results showed distinct cell context-dependent mechanisms for growth inhibition by sulfasalazine and erastin in hepatocellular carcinoma.
Keywords : sulfasalazine, ferroptosis, system xc, hepatocellular carcinoma


June 2019, 63 (3)
Full Text(PDF) Free

Social Network Service
Services

Cited By Articles
  • CrossRef (0)