The rising incidence of colorectal cancer (CRC) in recent decades has ranked it as the third most common cause of cancer-related mortality worldwide. The goal in this study was to determine the mechanism(s) by which VERU-111 alters the immune landscape in the tumor microenvironment to facilitate suppression of CRC. We found that VERU-111 halted wound healing in human colorectal carcinoma cell lines HCT-116 and DLD-1, caused cell cycle arrest, and disrupted microtubule assembly in vitro . We found that oral administration of VERU-111 reduced tumor burden and increased colon length relative to controls in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. We observed an increase in the number and frequency of CXCR3-expressing CD8-activated T cells and natural killer T (NKT) cells in the colon tumor microenvironment (CTM) in mice treated with VERU-111 as compared to vehicle control. VERU-111 increased the expression of NKG2D activating receptors and production of interferon-gamma (IFN-γ) ex vivo in mouse spleen-derived NK cells. Intriguingly, VERU-111 treatment reduced the frequency of macrophages and dendritic cells (DCs) expressing the programmed cell death ligand 1 (PD-L1) in the CTM and increased the frequency of macrophages, relative to controls. We also observed the induction of apoptosis by upregulation of the apoptotic markers BAX and cleaved caspase-3 (CC3), and TUNEL-positive apoptotic hotspots in tumors of mice treated with VERU-111. These findings suggest that VERU-111 effectively reduces tumor burden and suppresses CRC by recruiting effector T cells, NK cells, inducing apoptosis, and reducing myeloid cells expressing PD-L1 in CTM.
Mamun et al. (Mon,) studied this question.