The PI3K/AKT signaling pathway is an essential node in mammalian cells that controls cell growth, migration, proliferation, and metabolism[2]. Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. Expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1β, TNF-α, INF-γ, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways[3]. Rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in recessive dystrophic epidermolysis bullosa (RDEB) Squamous cell carcinoma(SCC) shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib[4]. Rigosertib induced obvious apoptosis in HEL and K562 cells, and the apoptotic effect was both time-dependent and dose-dependent manner (P<0.05). The low dose of rigosertib inhibited obviously the proliferation of HEL and K562 cells after treatment from 6 to 54h, Rigosertib arrested HEL and K562 cells into G2/M phase. In addition, Rigosertib obviously increased the expression of apoptosis-related proteins such as cleaved caspase 3 and PARP, and reduced the proliferation-related proteins such as BCL-2 and Cyclin D1. Rigosetib inhibited the activation of AKT-GSK signaling through decreasing the expression of AKT, pAKT(Ser473) and GSK-3α/β (S21/9)[5].
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