Research Perspective: Potential Role of Nitazoxanide in Ovarian Cancer Treatment. Old Drug, New Purpose?

Nicola Di Santo,Jessie Ehrisman

doi:10.3390/cancers5031163

Abstract

Among gynecological malignancies epithelial ovarian cancer (EOC) is the leading cause of death. Despite improvements in conventional chemotherapy combinations, the overall cure rate has remained mostly stable over the years, and only 10%–15% of patients maintain a complete response following first-line therapy. To improve the efficacy of ovarian cancer chemotherapy it is essential to develop drugs with new mechanisms of action. Compared to normal tissues, protein disulfide isomerase (PDI) is overexpressed in ovarian tumors. PDI is a cellular enzyme in the lumen of the endoplasmic reticulum (ER) of eukaryotes or the periplasmic region of prokaryotes. This protein catalyzes the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding. Selective inhibition of PDI activity has been exhibited both in vitro and in vivo anticancer activity in human ovarian cancer models. PDI inhibition caused accumulation of unfolded or misfolded proteins, which led to ER stress and the unfolded protein response (UPR), and in turn resulted in cell death. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. In this article, we propose that NTZ, acting as PDI inhibitor, may be a new and potent addition to the chemotherapeutic strategy against ovarian cancer.

Highlights

Epithelial ovarian cancer (EOC) is responsible for 4% of cancer-deaths in women and continues to be the leading cause of death from gynecologic malignancies in the United States [1]
In our paper we postulate that the inhibition chaperone function of protein disulfide isomerase (PDI), whose overexpression allows cancer cells to survive under harsh conditions, pushes the cells into an extreme autophagic process in order to cope with misfolded proteins and to relieve stress
In breast cancer xenograft mouse models, NTZ significantly suppressed tumor growth by inhibiting c-Myc and inducing apoptosis [17]. These findings support NTZ’s potential as a new, anti-tumor agent for the inhibition of c-Myc associated neoplasia, including ovarian cancer. In this concept paper we focused on PDI as an anti-cancer target for NTZ and aimed to draw organized connections between endoplasmic reticulum (ER) stress, URP and autophagy

Summary

Introduction

Epithelial ovarian cancer (EOC) is responsible for 4% of cancer-deaths in women and continues to be the leading cause of death from gynecologic malignancies in the United States [1]. A recent study accessing the development of drugs regulating c-Myc validated NTZ’s anti-Myc activity [17] Another previous study established that NTZ and the bromothiazolide RM4819 can inhibit the proliferation of colon cancer cells in vitro when bound to the protein glutathione. The purpose of this article is to propose, for the first time, the intriguing hypothesis that NTZ may sensitize cancer cells to stress-induced cell demise by blocking the PDI that under typical physiological circumstances restores ER homeostasis. In this fashion, we suggest that NTZ might enhance the efficacy of standard chemotherapy regiments in ovarian cancer patients and improve survival

Unfolded Protein Response in Tumor Development

Autophagy and Cancer

Autophagy and Cell Death

Thiazolides Compound

Findings

Conclusions