2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

Abstract

Prostate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2'-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-κB, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-κB activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models.

Tumor necrosis factor-related apoptosis-inducing ligand inhibits proliferation and induces apoptosis of prostate and bladder cancer cells

“…Shin et al showed that when prostate cells were treated in combination with tanshinone and TRAIL, miR135a-3p expression was upregulated and DR5 activity was induced, thereby increasing TRAIL-induced apoptosis of prostate cancer cells (10). Ismail et al showed that the combination of the anticancer drug, RG003 and TRAIL could enhance TRAIL-induced apoptosis of prostate cancer cells (11). Others have reported that metformin and evodiamine could enhance the effect of TRAIL on the apoptosis of human bladder cancer cells through downregulation of c-FLIP and Mcl-1 expression (12,13) via the mTOR/S6K1 signaling pathway.…”

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Prostate Cancer Cells after Treatment with Xanthohumol—A Natural Compound Present in Humulus lupulus L.

“…Natural and synthetic flavonoids can sensitize cancer cells by increasing their susceptibility to TRAIL-induced apoptosis. Flavonoids (flavonols, isoflavones, chalcones) play an important role in prostate cancer chemoprevention for they enhance TRAIL-mediated apoptosis [ 52 , 53 , 54 , 55 , 56 , 57 ]. Recent studies have revealed that chalcones, such as butein, chalcone, isobavachalcone, licochalcone-A, and xanthohumol, in combination with TRAIL cause an increase in the percentage of cell death in prostate cancer cells [ 43 ].…”

Modern aspects of the use of natural polyphenols in tumor prevention and therapy

“…The ability of quercetin to interact with the survivin promoter and prevent the expression of this protein was also found ( Özsoy et al, 2020 ). Information on the effect of flavonoids on various components of the signaling system of TRAIL-dependent apoptosis is given in Table 5 ( Ismail et al, 2015 ; Han et al, 2016 ; Park et al, 2016 ; Li et al, 2017 ; Xu et al, 2018 ; Kim et al, 2020 ; Wu et al, 2020 ; Huang et al, 2021 ).…”