There are two known subtypes of the so-called sigma receptors, Sigma1 and Sigma2. Sigma1 (encoded by the SIGMAR1 gene and also known as Sigma-1 receptor, S1R) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein that allosterically modulates the activity of its associated proteins. Sigma2, recently identified as transmembrane protein 97 (TMEM97), is an integral membrane protein implicated in cellular cholesterol homeostasis. A number of publications over the past two decades have suggested a role for both sigma proteins in tumor biology. Although there is currently no clinically used anti-cancer drug that targets Sigma1 or Sigma2/TMEM97, a growing body of evidence supports the potential of small-molecule compounds with affinity for these proteins, putative sigma ligands, as therapeutic agents to treat cancer. In preclinical models, these compounds have been reported to inhibit cancer cell proliferation, survival, adhesion, and migration; furthermore, they have been demonstrated to suppress tumor growth, to alleviate cancer-associated pain, and to exert immunomodulatory properties. Here, we will address the known knowns and the known unknowns of Sigma1 and Sigma2/TMEM97 ligand actions in the context of cancer. This review will highlight key discoveries and published evidence in support of a role for sigma proteins in cancer and will discuss several fundamental questions regarding the physiological roles of sigma proteins in cancer and sigma ligand mechanism of action.

Sigma-1 (σ₁) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether σ₁ receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, σ₁ antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of σ₁ inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice. Wild-type (WT) mice developed prominent cold (acetone test), mechanical (von Frey test), and heat hypersensitivity (Hargreaves test) after SNI. σ₁ receptor knockout (ခσ₁-KO) mice did not develop cold allodynia and showed significantly less mechanical allodynia, although they developed heat hyperalgesia after SNI. The systemic acute administration of the selective σ₁ receptor antagonist S1RA attenuated all three types of SNI-induced hypersensitivity in WT mice. These ameliorative effects of S1RA were reversed by the administration of the σ₁ agonist PRE-084, and were absent in σ₁-KO mice, indicating the selectivity of S1RA-induced effects. The opioid antagonist naloxone and its peripherally restricted analog naloxone methiodide prevented S1RA-induced effects in mechanical and heat hypersensitivity, but not in cold allodynia, indicating that opioid-dependent and -independent mechanisms are involved in the effects of this σ₁ antagonist. The repeated administration of S1RA twice a day during 10 days reduced SNI-induced cold, mechanical, and heat hypersensitivity without inducing analgesic tolerance during treatment. These effects were observed up to 12 h after the last administration, when S1RA was undetectable in plasma or brain, indicating long-lasting pharmacodynamic effects. These data suggest that σ₁ antagonism may have therapeutic value for the treatment of neuropathic pain induced by the transection of peripheral nerves.

The recent publication of the σ1R crystal structure is an important cornerstone for the derivation of more accurate activity prediction models. We report here a comparative study involving a set of more than 25,000 structures from our internal database that had been screened for σ1R affinity. Using the recently published crystal structure, 5HK1, two new pharmacophore models were generated. The first one, 5HK1–Ph.A, was obtained by an algorithm that identifies the most important receptor-ligand interactions including volume restrictions enforced by the atomic structure of the recognition site. The second, 5HK1–Ph.B, resulted from a manual edition of the first one by the fusion of two hydrophobic (HYD) features. Finally, we also docked the database using a high throughput docking technique and scored the resulting poses with seven different scoring functions. Statistical performance measures were obtained for the two models, comparing them with previously published σ1R pharmacophores (Hit Rate, sensitivity, specificity, and Receiver Operator Characteristic) and 5HK1–Ph.B emerged as the best one in discriminating between active and inactive compounds, with a ROC-AUC value above 0.8 and enrichment values above 3 at different fractions of screened samples. 5HK1–Ph.B also showed better results than the direct docking, which may be due to the rigidity of the crystal structure in the docking process (i.e., feature tolerances in the pharmacophore model). Additionally, the impact of the HYD interactions and the penalty for desolvating ligands with polar atoms may be not adequately captured by scoring functions, whereas HYD groups filling up such regions of the binding site are entailed in the pharmacophore model. Altogether, using annotated data from a large and diverse compound collection together with crystal structure information provides a sound basis for the generation and validation of predictive models to design new molecules.

Cell excitability is tightly regulated by the activity of ion channels that allow for the passage of ions across cell membranes. Ion channel activity is controlled by different mechanisms that change their gating properties, expression or abundance in the cell membrane. The latter can be achieved by forming complexes with a diversity of proteins like chaperones such as the Sigma-1 receptor (Sig-1R), which is one with unique features and exhibits a role as a ligand-operated chaperone. This molecule also displays high intracellular mobility according to its activation level since, depletion of internal Ca⁺² stores or the presence of specific ligands, produce Sig-1R’s mobilization from the endoplasmic reticulum toward the plasma membrane or nuclear envelope. The function of the Sig-1R as a chaperone is regulated by synthetic and endogenous ligands, with some of these compounds being a steroids and acting as key endogenous modifiers of the actions of the Sig-1R. There are cases in the literature that exemplify the close relationship between the actions of steroids on the Sig-1R and the resulting negative or positive effects on ion channel function/abundance. Such interactions have been shown to importantly influence the physiology of mammalian cells leading to changes in their excitability. The present review focuses on describing how the Sig-1R regulates the functional properties and the expression of some sodium, calcium, potassium, and TRP ion channels in the presence of steroids and the physiological consequences of these interplays at the cellular level are also discussed.

Allosteric modulators of sigma-1 receptor (Sig1R) are described as compounds that can increase the activity of some Sig1R ligands that compete with (+)-pentazocine, one of the classic prototypical ligands that binds to the orthosteric Sig1R binding site. Sig1R is an endoplasmic reticulum membrane protein that, in addition to its promiscuous high-affinity ligand binding, has been shown to have chaperone activity. Different experimental approaches have been used to describe and validate the activity of allosteric modulators of Sig1R. Sig1R-modulatory activity was first found for phenytoin, an anticonvulsant drug that primarily acts by blocking the voltage-gated sodium channels. Accumulating evidence suggests that allosteric Sig1R modulators affect processes involved in the pathophysiology of depression, memory and cognition disorders as well as convulsions. This review will focus on the description of selective and non-selective allosteric modulators of Sig1R, including molecular structure properties and pharmacological activity both in vitro and in vivo, with the aim of providing the latest overview from compound discovery approaches to eventual clinical applications. In this review, the possible mechanisms of action will be discussed, and future challenges in the development of novel compounds will be addressed.