A-class prostaglandins: Early findings and new perspectives for overcoming tumor chemoresistance

Abstract

The antiproliferative properties of cyclopentenone prostaglandins of the A-class have long been known. Considerable research has led to the elucidation of some of the mechanisms of action of these pleiotropic compounds. A-class prostaglandins or derived molecules (A-PG) may block the cell cycle, inhibit anti-apoptotic transcription factors, activate apoptotic cascades, induce a stress response and inhibit protein synthesis in a cell type-dependent manner. In addition, recent reports indicate that A-class PG may interact with various cellular detoxification systems and drug metabolizing enzymes used by cancer cells as mechanisms of chemoresistance. Some of these findings may open new perspectives for the development of strategies aimed at overcoming cancer resistance to widely used antitumor drugs. Here we outline the mechanisms of action for the antitumoral effects of PGA and related compounds, emphasizing those with impact on cellular defence systems which may contribute to cancer chemoresistance. The ability of A-PG to form covalent adducts with thiol groups in proteins and in glutathione is essential for their biological actions. Therefore, identification of the protein targets and elucidation of the interactions of A-PG with the glutathione biotransformation system will be critical for understanding the antitumoral effects of these compounds per se or through their ability to sensitize cancer cells towards other drugs.

Introduction

Tumor chemoresistance is one of the major problems encountered during cancer chemotherapy and overcoming this adverse situation is an important challenge nowadays [1]. Combination therapies of tailored drugs targeting tumor type-specific mechanisms of tumorigenesis or resistance are showing improved performance and offering new strategies [2]. The anti-tumoral properties of prostaglandins of the A-class have been the subject of intense study in the search for compounds with novel mechanisms of action which could display antitumoral effects on their own or potentiate the effects of some of the widely used anti-cancer drugs.

Prostaglandins of the A-class were identified in human seminal plasma in the 1960s [3] and were detected at low nanomolar concentrations in human plasma [4]. Formation of A-type PG occurs in vivo by dehydration of their parent PG, that is PGE₁ or PGE₂, formed in turn by the sequential action of cyclooxygenase (COX) enzymes and PGE synthases on unsaturated fatty acids of 20 carbon atoms [5], [6]. Organic synthesis of these compounds greatly facilitated the assessment of their effects in diverse biological systems. Notably, it was found that A-class PG were able to inhibit the proliferation of tumor cells in vitro, including melanoma and leukemia cells, and display antitumor activity against several kinds of tumors in vivo [7], [8], [9]. A-class PG were found to block the cell cycle and induce apoptosis in various cancer cell lines and, in some cases, potentiate the effects of other anticancer drugs [10], [11], [12]. In addition, A-class PG were shown to enhance cell differentiation in certain tumor cell lines [13], [14]. A-class PG have also shown antiviral activity against poliovirus, Sendai and HIV virus, among others [15], [16]. The mechanisms of these effects may be multiple and involve the interaction of A-class PG with both cellular and viral targets. Early studies identified the induction of a heat shock response and the inhibition of transcription factor nuclear factor-kappa B (NF-κB) as important events in the antiviral effect [15], [17]. More recently other mechanisms have been put forward including interference with viral morphogenesis [18]. Moreover, the ability of these compounds to inhibit NF-κB drew attention to their potential as anti-inflammatory agents and indeed, anti-inflammatory effects of A-class PG have been observed both in cellular and animal models of inflammation [19], [20]. Here again, the involvement of other potential targets including the inhibition of transcription factor activator protein 1 (AP-1) or the activation of peroxisome proliferator activated receptor gamma (PPARγ), need to be considered [21], [22], [23]. The observation of these effects led to the definition of the three main potentially therapeutic properties of these PG, namely antiproliferative, antiviral and anti-inflammatory.

From the early studies it was noted that the particular chemical structure of these compounds and their electrophilic nature played an important role in their biological activity [13], [24]. A-class PG possess a cyclopentenone structure bearing an α,β-unsaturated carbonyl group and one or more electrophilic carbons which is key for activity. Thus, PG with cyclopentenone structure (cyPG) may suffer nucleophilic attacks and form covalent adducts with nucleophiles, including several residues in proteins and with the cysteine residue of the tripeptide glutathione (see [25] for review), through a reaction known as Michael addition (Fig. 1). In recent years, the use of cyPG has helped unveil novel mechanisms of cellular regulation and signal transduction common to other electrophilic species or to redox-modulating agents [23], [26], [27]. It should be noted that their reactivity may be one of the advantages but also of the drawbacks of the use of cyPG in clinical settings and further work is needed to elucidate their antitumoral potential. Although initial studies on the properties or A-class PG revealed antitumoral effects in preclinical studies in vivo, as far as we know the use of these compounds has not reached the clinical practice yet. However, in the last few years there has been a renewed interest in the potential clinical use of these compounds and several new formulations of cyPG analogs, with improved bioavailability and the possibility of a more targeted administration, are under study [20]. In addition, the functional cyclopentenone moiety is shared by a number of natural and synthetic products which are showing antitumoral properties and offering novel leads for drug design [28].

In this review we address the mechanisms of the antitumoral action of A-series PG and various derived molecules, which we will refer in general as A-PG, making particular emphasis on their ability to overcome cancer chemoresistance in experimental settings. Moreover, given the fact that covalent modification of proteins constitutes the main mechanism for cyPG action, we discuss the importance of target identification to open new perspectives for the potential use of these or related compounds as therapeutic tools.