TGF-β INCREASES CYTOTOXIC EFFECT AND SENESCENCE INDUCED BY PI3K/ AKT/ MTOR INHIBITOR IN HUMAN COLORECTAL CANCER CELLS

Although NVP-BEZ235 and XAV-939 have been shown a promising result in the treatment of colorectal cancer (CRC), our data is little with regard to the effect of environmental cytokine on this drugs. In order to explore the reaction of CRC to this novel therapy, the current study proposes to investigate the inhibitory effect of NVP-BEZ235 and/or XAV-939 in CRC cells in combination with TGF-β as a tumor environmental cytokine to analyze their effect on cancer cell proliferation, cell death and expression of cancer promoting genes. The cells were treated with single or combination of NVP-BEZ235, XAV-939 and TGF-β. Cell viability was evaluated by MTT assay. Flow cytometry method was used to determine cellular death. Real-time PCR was utilized to identify the effect of treatments on expression of snail, slug, C-myc and notch1 genes. The results revealed that NVP-BEZ235 inhibited CRC cells proliferation and induced senescence cells more than XAV-939. Although, XAV-939 increased cellular death and inhibited senescence induction of CRC cells better than NVP-BEZ235. TGF-β pretreatment sensitizes CRC cells to the cytotoxic effect of NVP-BEZ235 and XAV-939. Real-time PCR analysis showed that resistance cells to NVP-BEZ235 increased expression of slug. Expression of notch enhanced remarkably when cells treated with both NVP-BEZ235 and XAV-939. The results of the present study demonstrated that presence of anti-inflammatory cytokine like TGF-β augments the inhibitory effect of XAV-939 or especially NVP-BEZ235.