Sigma-1 Receptor Ligands for CNS Cancer Treatment.

The development of new and effective anticancer drugs remains a significant challenge owing to several factors, including the nonspecific nature of conventional therapies, the tendency of cancer cells to develop multidrug resistance, and the difficulty drugs face in crossing specialized barriers such as the blood-brain barrier (BBB) for cancers affecting the central nervous system (CNS). Repurposing existing, approved drugs for new therapeutic uses presents a promising approach to addressing these challenges at lower costs and in shorter time frames. Sigma receptors, particularly sigma-1, are widely distributed in the CNS and have garnered attention in neurodegeneration and pain research. Despite being overexpressed in many cancers, their potential role in cancer treatment has been largely overlooked. Sigma receptors are appealing therapeutic targets because they regulate cell survival, proliferation, and differentiation. Growing evidence links the sigma-1 receptor to the regulation of autophagy, a critical process in cancer development. Several neuroactive drugs, including haloperidol, rimcazole, fluoxetine, and donepezil, act as sigma receptor ligands and may offer anticancer benefits. This review explores the potential of these drugs for treating cancers, particularly those of the CNS, by examining their autophagic, anticancer, and sigma-receptor activities.