A Novel DRD2 Antagonist, SD2-2305, Exerts Anticancer Effects in Colorectal Cancer Cells through G1 Arrest and Caspase-Dependent Apoptosis

Colorectal cancer (CRC) remains difficult to treat due to challenges in early detection and the development of therapeutic resistance. Dopamine receptor D2 (DRD2) plays a critical role in regulating cell proliferation and apoptosis in various solid tumors. Given the relatively high levels of dopamine in the gastrointestinal tract, colorectal tumors may be particularly susceptible to DRD2-mediated signaling. In this study, we evaluated the anticancer activity of a newly synthesized DRD2 antagonist, SD2-2305, and investigated its underlying mechanisms in human CRC cell lines HCT116 and HT-29. SD2-2305 reduced cell viability in a time- and dose-dependent manner. Induction of apoptosis was confirmed by Annexin V/PI staining and immunoblot analysis, with activation of caspase-3, caspase-7, and caspase-9, although no significant changes were observed in the expression of Bcl-2 family proteins. Furthermore, SD2-2305 induced G1 phase cell cycle arrest, accompanied by downregulation of Cyclin A, Cyclin B, CDK1, and CDK2, and upregulation of p21. While key survival pathways (JAK2/STAT3, PI3K/Akt, and MAPK) remained relatively unaffected, SD2-2305 modulated growth factor receptors post-transcriptionally, decreasing HER2/ErbB2 and increasing TGF-beta receptor 1 expression. Collectively, these findings demonstrate that the DRD2 antagonist SD2-2305 exerts potent anticancer effects through the induction of cell cycle arrest and apoptosis, and suggest that the anticancer activity of SD2-2305 is associated with coordinated modulation of growth factor receptor signaling and cell-cycle regulators in CRC cells.