Application of self-assembly peptides targeting the mitochondria as a novel treatment for sorafenib-resistant hepatocellular carcinoma cells

Tae Ho Hong,Ja-Hyoung Ryu,Ha-Eun Hong,Kyung Hee Lee,Ho Joong Choi,M T Jeena,Say-June Kim,Kee-Hwan Kim,Ok-Hee Kim

doi:10.1038/s41598-020-79536-z

Abstract

Currently, there is no appropriate treatment option for patients with sorafenib-resistant hepatocellular carcinoma (HCC). Meanwhile, pronounced anticancer activities of newly-developed mitochondria-accumulating self-assembly peptides (Mito-FF) have been demonstrated. This study intended to determine the anticancer effects of Mito-FF against sorafenib-resistant Huh7 (Huh7-R) cells. Compared to sorafenib, Mito-FF led to the generation of relatively higher amounts of mitochondrial reactive oxygen species (ROS) as well as the greater reduction in the expression of antioxidant enzymes (P < 0.05). Mito-FF was found to significantly promote cell apoptosis while inhibiting cell proliferation of Huh7-R cells. Mito-FF also reduces the expression of antioxidant enzymes while significantly increasing mitochondrial ROS in Huh7-R cells. The pro-apoptotic effect of Mito-FFs for Huh7-R cells is possibly caused by their up-regulation of mitochondrial ROS, which is caused by the destruction of the mitochondria of HCC cells.

Highlights

There is no appropriate treatment option for patients with sorafenib-resistant hepatocellular carcinoma (HCC)
Mito-FF consists of diphenylalanine, triphenylphosphonium (TPP), and pyrene, which serve as β-sheet-forming building blocks, mitochondrial targeting moieties, and fluorescent probes, respectively
Western blot analysis was complemented to compare the expression of p53, cell proliferation-related proteins (p-AKT and phosphorylated extracellular signal-regulated kinase-1 (p-ERK)) and antioxidant proteins (SOD, glutathione peroxidase (GPx), and catalase) in each type of HCC cells (Fig. 1D)

Summary

Introduction

There is no appropriate treatment option for patients with sorafenib-resistant hepatocellular carcinoma (HCC). The pro-apoptotic effect of Mito-FFs for Huh7-R cells is possibly caused by their up-regulation of mitochondrial ROS, which is caused by the destruction of the mitochondria of HCC cells. Abbreviations GPx Glutathione peroxidase Huh7-S cell Sorafenib-sensitive Huh[7] cell Huh7-R cell Sorafenib-resistant Huh[7] cell Mito-FF Mitochondria-accumulating phenylalanine dipeptide with triphenyl phosphonium p-ERK Phosphorylated extracellular signal-regulated kinase SOD Superoxide dismutase BAX Bcl-2-like protein 4 Bcl-xL B-cell leukemia-extra large c-Cas[3] Cleaved caspase-3 c-Cas[9] Cleaved caspase-9 PARP Poly-ADP (adenosine diphosphate)-ribose polymerase NAC N -Acetyl-l-cysteine ROS Reactive oxygen species. These limitations with sorafenib have compelled the need to develop novel or supplementary drugs for patients that are adversely affected by sorafenib

Methods

Results

Conclusion