Abstract

Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. β-Phenethyl isothiocyanate (PEITC) exhibits chemoprevention and chemotherapeutic activities against many human cancers. The molecular mechanism underlying its action on osteosarcoma is still unknown. This study was aimed at investigating the effect of PEITC on human osteosarcoma both in vitro and in vivo. The results showed that PEITC reduced cell viability, inhibited proliferation, and caused G2/M cell cycle arrest in four human osteosarcoma cell lines (MNNG/HOS, U-2 OS, MG-63, and 143B). Then, we found that PEITC altered iron metabolism related to the processes of iron import, storage, and export, which resulted in increased labile iron. Expectedly, PEITC caused oxidative stress as a consequence of GSH depletion-inducing ROS generation and lipid peroxidation. Multiple cell death modalities, including ferroptosis, apoptosis, and autophagy, were triggered in human osteosarcoma cells. Three MAPKs (ERK, p38, and JNK) were all activated after PEITC treatment; however, they presented different responses among the four human osteosarcoma cell lines. ROS generation was proved to be the major cause of PEITC-induced decreased proliferative potential, altered iron metabolism, cell death, and activated MAPKs in human osteosarcoma cells. In addition, PEITC also significantly delayed tumor growth in a xenograft osteosarcoma mouse model with a 30 mg/kg administration dose. In conclusion, this study reveals that PEITC simultaneously triggers ferroptosis, apoptosis, and autophagy in human osteosarcoma cells by inducing oxidative stress.

Highlights

  • Osteosarcoma (OS) is a primary tumor of the skeleton ordinarily manifesting as malignant mesenchymal cells producing osteoid or immature bone [1]

  • Our results show that Phenethyl isothiocyanate (PEITC) inhibits cell proliferation and triggers different cell death modalities including ferroptosis, apoptosis, and autophagy in four human OS cell lines

  • The results indicated that PEITC significantly inhibited the viability of human OS cells in concentration- and time-dependent manners (Figure 1(a))

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Summary

Introduction

Osteosarcoma (OS) is a primary tumor of the skeleton ordinarily manifesting as malignant mesenchymal cells producing osteoid or immature bone [1]. Most of the cases range from 10 to 25 years of age. A large number of chemotherapeutic agents are in use, most of patients still need limb surgical resection and undergo lung metastasis [2]. There is no obvious improved outcome in OS patients [3, 4]. Alternative therapeutic approaches for OS patients are urgently needed to improve their life quality and increase their hope for future [5,6,7]. One of the promising explorations is to screen potential anticancer agents from natural products that can endow the marvelous power of plant phytochemicals to human health

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