Anti-cancer Effects And The Mechanisms Of New Sulindac Derivatives

Members of the nuclear receptor superfamily are critical regulators of cell growth,proliferation,differentiation,metabolism,inflarnation and apoptosis.Retinoid X receptor-a(RXRa)a unique and important member of the nuclear receptor superfamily,plays critical roles in many biological and pathological processes such as growth,differentiation,metabolism and death.Abnormal expression,fumction and localization of RXRa are implicated in the development of a number of diseases,such as cancer.RXRa is also a intruging and validated drug target for pharmacologic interventions.Our laboratory previously discovered that the N-terminally truncated RXRa(tRXR?),which,was highly expressed in many types of tumor cells,interacted with p85a to activate AKT survival pathway and promote tumor cell grovrth.In addition,we found that non-steroidal anti-inflammatory drug(NSAID)sulindac could bind to tRXRa,inhibit the interaction of tRXRa and p85a and induce tumor cell apoptosis.Subsequently,we designed and synthesized analogs of Sulindac including K-80003 and K-8008 that exhibit improved RXR?-binding efficacy and selectivity.In this study,we report the design,synthesis and biologieal evaluation of a series of K-80003 derivatives.Our results showed that 9q,a derivative of K-80003,can bind RXRa and induce apoptosis of cancer cells in a RXRa-dependent manner.Moreover,we found that 9q can cause cell cycle arrest at G2/M phase,which is also mediated by RXRa.In addition,we found that 9q could induce the activation of MEK/ERK signaling pathway,and the tumor inhibition effect was significantly enhanced after combined with the MEK inhibitor Cobimetinib.Moreover,RXRa was involved in the regulation of MEK/ERK signaling pathway.We also employed structure-based virtual screening to identify RXRa modulators that can bind and stabilize RXRa-LBD tetramers and identified atorvastatin(also known as Lipitor)as a non?canonical ligand of RXRa that acts to stabilize the RXRa tetrameric conformation to regulate RXRa nongenomic actions.Our results suggested that atorvastatin could be optimized as a lead compound targeting RXRa for anticancer therapy.