Introduction

Salinomycin is a carboxylic polyether ionophore which was isolated from the culture supernatant of the bacterium Streptomyces albus in 1974 [1]. Structurally, it is composed of a penta-cyclic molecule with a unique tricyclic spiroketal ring system and a unsaturated six-membered ring (Fig. 1). Its lipophilic property enables salinomycin to act in cytoplasmic and mitochondrial membranes as an ionophore with a strong preference for potassium. Therefore, it promotes cellular and mitochondrial potassium efflux and inhibits mitochondrial ox-idative phosphorylation [2, 3].

Salinomycin exhibits a broad antimicrobial spectrum against gram-positive bacteria including mycobacteria, Bacillus subtilis, Staphylococcus aureus and some filamentous fungi, but not against gram-negative bacteria and yeast [1]. Moreover, salinomycin has been shown to kill protozoan parasites, such as Plasmodium falciparum and Eimera spp., that cause severe cocci-diosis in the livestock and poultry industries. Owing to its anti-parasite properties, salino-mycin has been used to control coccidiosis in parasite-infected chickens and cows [4, 5].

More recently, the anticancer property of salinomycin has been recognized based on its ability to induce apoptosis and cause growth inhibition in diverse types of apoptosis- and che-motherapeutic-resistant cancer cells [6]. Salinomycin-mediated apoptosis in these cells is independent of known mediators of the cell death signal pathway, such as the p53 tumor suppressor protein, the 26S proteasome and the CD95/DC95 ligand system. This drug also triggers apoptosis by overcoming ATP-Binding Cassette (ABC) transporter-mediated multi-drug resistance, as was observed in the case of KG-1a human leukemia cells [7, 8]. Salinomy-

cin caused massive tumor cell apoptosis and associated regression of breast tumor growth and metastasis in vivo in a mouse xenograft tumor model [9]. In fact, in high-throughput screening of ~16,000 small molecule chemicals, breast cancer stem cells (CSCs) were found to be inhibited selectively by salinomycin [9]. CSCs are a subpopulation of cells within the tumor mass that are thought to account for cancer recurrence by virtue of their refractivity to cytotoxic cancer treatment agents such as radiation and a wide variety of chemotherapeutic agents. Susceptibility of CSCs to salinomycin bolsters the possibility that this drug may target treatment-resistant advanced human cancers. Delineation of the mechanism(s) that underlies cancer cell apoptosis by salinomycin is needed in order to rigorously evaluate the potential of this drug as a novel cancer therapeutic.

Figure 1. Structural formula of salinomycin. It has a molecular mass of 751 Da and a molecular formula of C^HjqO,,.

Apoptosis is a regulated cell death process that requires the cascaded activation and execution of a series of regulatory molecules and cysteine-aspartic proteases, known as caspases [10]. Stress agents, such as reactive oxygen species (ROS), ultraviolet radiation, viral infections, and anticancer agents are well-characterized apoptosis triggers. Mitochondria are the primary site of origin for the initiating signals of apoptosis, although a death receptor-dependent extramitochondrial apoptotic pathway also exists. Mitochondrially originated apoptotic signals include a change in the electron transport system, loss of mitochondrial membrane potential (MMP, A^m), failure of Ca2+ flux homeostasis, generation of ROS, and release of caspase activators. Early apoptosis is invariantly marked by a breakdown in the MMP, which precedes DNA fragmentation in all cell types and under all types of apoptotic stimuli [11]. Production of endogenous ROS as mitochondrial byproducts of respiration is tightly controlled by MMP. Disruption in the ROS homeostasis plays a critical role in the regulation of mitochondrial dysfunction and apoptotic events [12].

Prostate cancer initially responds to androgen deprivation, which is a standard-of-care therapy when the androgen-dependent malignant cells meet with apoptotic death in an environ ment of low, castrate-level circulating androgens. Relapse, however, is a common occurrence at which point the recurrent cancer cells are castration resistant and have the ability to progress on chemotherapeutics to become completely therapy resistant [13-15].

In this chapter, we describe our recent findings that salinomycin induces apoptosis of prostate cancer cells by elevating oxidative stress through intracellular ROS production, which leads to the disruption of mitochondrial function and subsequent release of cytochrome c to the cytosol, activation of caspase-3, and cleavage of PARP-1 in androgen-independent, che-motherapeutic-refractive PC-3 human prostate cancer cells [16].

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