Nutrient deprivation enhances the cytotoxic effects of a sulfonamide-chalcone hybrid in PC-3 prostate cancer cells

Hybrid molecules integrating different pharmacophoric motifs have emerged as a promising strategy in anticancer drug discovery. In this study, we report for the first time the biological effects of a sulfonamide-chalcone hybrid in the PC-3 prostate cancer cell line under standard culture conditions and nutrient deprivation. The molecular design of SSC185 (µ-(2,5-dichloro-N-{4-[(3E)-4-(3-nitrophenyl)buta-1,3-dien-2-yl]phenyl}benzenesulfonamide) incorporates an α,β-unsaturated system conjugated to the chalcone scaffold together with a sulfonamide moiety, structural features frequently associated with modulation of cancer-related signaling pathways. Results demonstrated that SSC185 reduced the MTT signal of PC-3 cells in a concentration- and time-dependent manner, with IC₅₀ values of 24.69 µM at 24 h and 18.9 µM at 72 h, and exhibited enhanced activity under serum-deprived conditions, with an IC₅₀ of 4.20 µM. Complementary studies employing pharmacological modulators of autophagy, apoptosis, redox status, and proteostasis were conducted to further characterize the compound's activity. SSC185 increased SQSTM1/p62 and LC3B-I levels without detectable changes in LC3B-II levels or increased acidic vesicle formation, accompanied by reduced AKT/RPS6 signaling and mitochondrial dysfunction. These molecular alterations were associated with the cellular response to SSC185, while nutrient deprivation markedly enhanced its activity in PC-3 cells, indicating that the cellular nutritional context influences the response to the compound.