Small Molecule Antagonists of the σ-1 Receptor Cause Selective Release of the Death Program in Tumor and Self-Reliant Cells and Inhibit Tumor Growth in Vitro and in Vivo

Abstract

The acquisition of resistance to apoptosis, the cell's intrinsic suicide program, is essential for cancers to arise and progress and is a major reason behind treatment failures. We show in this article that small molecule antagonists of the -1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic -1 agonists (؉)-SKF10,047 and (؉)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even receptor-rich neurons are resistant to the apoptotic effects of antagonists, cells that can promote autocrine survival such as lens epithelial and microvascular endothelial cells are as susceptible as tumor cells. Cellular susceptibility appears to correlate with differences in receptor coupling rather than levels of expression. In susceptible cells only, antagonists evoke a rapid rise in cytosolic calcium that is inhibited by -1 agonists. In at least some tumor cells, antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3-kinase pathway signaling. Systemic administration of antagonists significantly inhibits the growth of evolving and established hormone-sensitive and hormone-insensitive mammary carcinoma xenografts, orthotopic prostate tumors, and p53-null lung carcinoma xenografts in immunocompromised mice in the absence of side effects. Release of a receptor-mediated brake on apoptosis may offer a new approach to cancer treatment.

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

“…Also other σ-2 ligands, haloperidol and rimcazole, induced a rapid rise in the lysosomal pH in MCF-7 cells when added at concentrations with anti-proliferative effects comparable to 8 μM siramesine, i.e., 50 μM and 20 μM, respectively. 10,15 Contrary to the siramesine-induced rise in the lysosomal pH that persisted for up to 16 h (data not shown), the lysosomal pH gradient was re-established in haloperidol-and rimcazole-treated cells already 4 h after the addition of the drug (Fig. 1A).…”

“…13 σ-2 selective ligands (e.g., siramesine, CB-184, CB-64D, ibogaine and PB28) as well as non-selective ligands that bind both σ-1 and σ-2 receptors (haloperidol, rimcazole and SR31474A) display anti-tumor activity in many tumor cell lines in vitro as well as in tumor xenografts in vivo. [14][15][16][17] Siramesine is the most potent anti-cancer agent among the known σ-ligands. It kills tumor cell lines originating from breast, cervix, lung, prostate and connective tissue at low micromolar concentrations in vitro and its per oral administration shows potent anti-tumor activity against fibrosarcoma and breast carcinoma grafts in mice.…”

Methyl gallate and chemicals structurally related to methyl gallate protect human umbilical vein endothelial cells from oxidative stress

“…In addition to the calcium regulation, antagonists of Sig-1R inhibit the activity of PKB/Akt in an apparently calcium-independent manner. Thus, PLC activation and PKB/Akt inhibition in response to Sig-1R antagonists appear to constitute biochemically separable signal transduction responses, which are to restrain the proapoptotic signaling pathway and to stimulate a prosurvival signaling cascade (Spruce et al, 2004). Based on these results that Sig-1R regulates apoptosis and survival signaling pathways for the cell survival, cellular protective ability of meGAL against oxidative stress may be linked to the induction of Sig-1R gene by meGAL.…”

“…RCC1 is known to be involved in cell cycle, cell proliferation, nuclear transport and the inhibition of the Ran-GEF activity of RCC1 was reported to cause cell death through premature chromatin condensation (Nishijima et al, 2003;Zheng, 2004). Sig-1R also has the variety of functions such as a novel opioid receptor, cellular proliferation and modulations of ion channel, ankyrin, Ca 2+ and sphingolipid levels (Hayashi and Su, 2001;Aydar et al, 2004;Spruce et al, 2004). Similar to RCC1, small molecule antagonists of Sig-1R inhibit tumor cell survival by activating programmed cell death (Zheng, 2004).…”

Neuroactive steroids protect retinal pigment epithelium against oxidative stress

“…This synergistic effect could be related to the fact that BD1047 also presented an affinity for the σ 2 receptor (K i = 47 nM). Because σ 1 receptors appear to be antiapoptotic and σ 2 receptors are proapoptotic [17,18], the activation of σ 1 receptors by an agonist and the inhibition of σ 2 receptors by an antagonist should lead to a synergistic effect in terms of cells protection. Indeed, cell protection does not occur when the σ 1 receptors are already blocked by an antagonist, as in the case of the pretreatment with BD1047.…”