The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization.

Raquel Lima,Madalena Pedro,Franklim Marques,Ana Gomes,Nuno Mendes,M Vasconcelos,Diana Sousa,Emília Sousa,Rune Matthiesen,Madalena Pinto

doi:10.3390/molecules23123301

Abstract

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport.

Highlights

Cholesterol is an essential component at the basis of a wide array of cellular functions [1].Mainly found at the plasma membrane, cholesterol plays a structural role in membrane fluidity and membrane’s protein activity [2]
This study showed that TXA1.HCl upregulates steroid biosynthesis in vitro and affects the expression of proteins involved in steroid trafficking
Altered cholesterol localization has been previously shown to result in mTOR inhibition and in the induction of autophagy

Summary

Introduction

Cholesterol is an essential component at the basis of a wide array of cellular functions [1].Mainly found at the plasma membrane, cholesterol plays a structural role in membrane fluidity and membrane’s protein activity [2]. Cholesterol is an essential component at the basis of a wide array of cellular functions [1]. Cholesterol cellular levels are highly controlled by a tightly regulated network of cell signaling and lipid transfer systems involving mechanisms for de novo synthesis and esterification and synthesis of LDLR (low-density lipoprotein receptor) to internalize extracellular cholesterol [1,3,4]. Alterations in cholesterol homeostasis impact many key signaling pathways, namely cell growth and survival, being associated with several different pathologies, namely cancer [5]. Changes in cholesterol normal levels may be involved in carcinogenesis and tumor development in several cancers, acting in some cases as promoters, while in others as suppressors [5,6]

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