Abstract
Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy.
Highlights
Sigma receptors have been recently referred in cancer pathophysiology
Ligands can be explained via a multitude of hypothesis, broad structural diversity among σR ligands can be explained via a multitude of hypothesis, the the most prevalent of whom suggests that receptors possessdynamic dynamicstructures, structures,sufficiently sufficiently flexible flexible most prevalent of whom suggests that thethe receptors possess to accommodate all these structurally diverse compounds
The following phenylalkylamines analogs with general type XI [141], XII [142] and XIII [143] have been reported for their antiproliferative activity and due to the similarities of their scaffold with compounds VIII and IX, it can be assumed that they act as σR ligands, their binding affinities have not been investigated yet (Figure 11)
Summary
Sigma receptors (σRs) have been recently referred in cancer pathophysiology. Initially, they were identified as opiate receptors and their description was based on the pharmacological evaluation of (±)-SKF-10,047 (N-allylnormetazocine), morphine and ketazocine in the chronic spinal dog model [1]. There is considerable evidence of antiproliferative and cytotoxic activity for σ1R antagonists, σ2R agonists and mixed σ1R/σ2R ligands [20,21,22,23,26], the mechanism of action is still elusive Both σR types are overexpressed in numerous human cancer tissues, such as small- and non-small-cell lung carcinoma [24,32], large-cell carcinoma (NCI-H1299 and NCI-H838) [33], renal carcinoma [24], colon carcinoma (HCT-15 and HCT-16) [34], sarcoma [33], brain tumors (CNS U51) [35], breast cancer Many σR ligands with various scaffolds have been evaluated as cytotoxic in a variety of cancer cell lines by activating caspase-dependent and caspase-independent apoptosis. This deviation in the mechanism of action can be used to define σR ligands as agonists or antagonists.
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