The Synergistic Apoptotic Interaction of Indole-3-Carbinol and Genistein with TRAIL on Endometrial Cancer Cells

Abstract

Induction of apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. The purpose of this study was to determine whether Indole-3-Carbinol (I3C) and Genistein in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis in endometrial cancer cell (Ishikawa) and to assess apoptotic mechanism. The MTT assay and flow cytometry were performed to determine cell viability and cell cycle. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay, annexin V binding assay and western blot analysis. There was no effect in cell growth inhibition and cell cycle progression alone or in two-combination. However, the treatment of I3C and Genistein followed by TRAIL showed significant cell death and marked increase in sub-G1 arrest. Three-combination treatment revealed elevated expression of DR4, DR5 and cleaved forms of caspase-3, caspase-8, PARP. The Flip was found down regulated. Moreover, increase in caspase-3 activity and DNA fragmentation indicated the induction of apoptosis. The results indicate that I3C and Genistein with TRAIL synergistically induced apoptosis via death receptor dependent pathway. Our findings might provide a new insight into the development of novel combination therapies against endometrial cancer.

A Narrative Review of the Role of Diet and Lifestyle Factors in the Development and Prevention of Endometrial Cancer

“…I3C and/or its metabolites also modulate some metabolic pathways that are critical to cancer cell survival [ 358 ] and DIM may interrupt oestrogen receptor signalling in EC cells [ 365 ]. In combination with the soy isoflavone genistein, programmed cell death is enhanced through increased TRAIL action, a protein that has cancer-cell-killing properties [ 366 ].…”

TRAIL-Sensitizing Effects of Flavonoids in Cancer

“…Genistein, a major isoflavone compound in soybeans and soy products, has been reported to enhance TRAIL-induced apoptosis in the endometrial cell line Ishikawa and in TRAIL-resistant A549 human lung adenocarcinoma cells by unleashing the death receptor signaling pathway (increase in DR4 and DR5, reduction in c-FLIP) and by inhibiting autophagic flux, respectively [71,72]. Biochanin-A, a dietary isoflavone found in soy and red clover, was reported to overcome resistance to TRAIL in the prostate cancer cell lines LNCaP and DU145.…”

Phytoestrogen genistein inhibits EGFR/PI3K/NF-kB activation and induces apoptosis in human endometrial hyperplasial cells

“…Genistein has been identied as the predominant isoavone in soybean enriched foods. 1 In numerous epidemiological studies, this phytoestrogen has great potential as an inexpensive, bioavailable chemotherapeutic agent with high antioxidant capacity as well as being effective in the treatment of different types of cancer and diseases, like breast cancer, 2 prostate cancer, 3 ovarian cancer, 4 colon cancer, 5 endometrial cancer 6,7 and endometriosis. 8 Several investigations in various in vitro and in vivo models have demonstrated that genistein modulates estrogen sensitive parameters in selective estrogen receptor modulator (SERM) like manner and it may be referred as a phyto-SERM.…”