Abstract
Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-X(L), survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII-positive blood vessels and hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappaB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer.