Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.

Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge in the treatment of advanced-stage prostate cancer, particularly among American men. Despite current therapeutic options, disease progression and resistance continue to limit patient outcomes. Therefore, the exploration of novel therapeutic strategies is urgently needed. This study investigates the anticancer potential of cambinol, a selective inhibitor of neutral sphingomyelinase 2, alone and in combination with apalutamide, in mCRPC cells. mCRPC cells were treated with different concentrations of cambinol and apalutamide. Cell viability assay was performed to determine the half-maximal inhibitory concentration for each drug. The effects of cambinol on colony formation and cell migration were assessed. Protein expression levels of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin signaling components were evaluated using immunoblotting analysis. Cambinol treatment at 0.1× and 0.5× half-maximal inhibitory concentration significantly reduced cell viability and colony formation in a dose-dependent manner, underscoring its antiproliferative potential. Combined treatment with cambinol and apalutamide led to a marked decrease in cell migration, suggesting synergistic effects in limiting metastatic behavior. Western blot analysis revealed the downregulation of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin, indicating suppression of key survival and proliferation pathways. This study provides new insights into the multifaceted anticancer effects of cambinol in mCRPC cells, including inhibition of cell viability, colony formation, and migration. The observed molecular changes support its role in modulating critical signaling pathways. These findings warrant further investigation into the therapeutic potential of cambinol, both as a monotherapy and in combination with standard therapies, for the treatment of mCRPC. SIGNIFICANCE STATEMENT: This study aimed to evaluate the antitumor effect of cambinol, a selective inhibitor of neutral sphingomyelinase 2, and its combination with apalutamide as a potential therapeutic strategy for metastatic castration-resistant prostate cancer.