Structural And Biological Analysis Of Berberine's Inhibition Of Colon Cancer Growth Through Retinol X Receptors And Related Drug Modification

Retinol X receptor(RXR?)is an important member of the nuclear receptor superfamily and plays an important role in the regulation of cell proliferation,apoptosis,differentiation,and development of life activities.Our research group first proved that berberine,is a specific activator of RXR?.Berberine could inhibit the proliferation of colon cancer cells by regulating the downstream genes related to cell cycle and degrading ?-catenin in the nucleus through RXR?.Based on this research,we futher found that berberine mediates up-regulation of E3 ubiquitin ligase c-Cbl expression via RXR?,promotes c-Cbl nucleation,enhances the binding of ?-catenin and c-Cbl in the nucleus,and induces c-Cbl-mediated ?-catenin nuclear degradation.The mechanism of berberine inhibiting the proliferation of colon cancer cells with RXRa as the target was further improved.Traditional Chinese medicine is the precious treasure of China.It has many years of history in anti-cancer and has achieved remarkable results.Natural products and their synthetic analogs provide a rich source for development of new anti-cancer drugs.Our previous study indicated that berberine inhibit colon cancer growth through RXR?.Berberine is a safe drug with high tumor selectivity,but also has some limitations,such as high dosage and low bioavailability.In this.study,we designed and synthesized a series of berberine analogues based on the interaction mode of berberine and RXRa and found the structural characteristics that affect the biological activity of berberine analogues by studying the structure-activity relationship.Among these analogues,B-12 was identified as the optimal RXRa activator.Much more efficiently than berberine,B-12 bound and altered the conformation of RXR?/LBD,thereby suppressing Wnt/?-catenin pathway and colon cancer cell growth via RXRa mediation.It also shows better performance than berberine in xenograft mouse models through regulation of RXRa and not induce obvious hepatorenal toxicity or hepatomegaly as most anti-tumor drugs did.In addition,B-12 not only reserved the tumor selectivity of berberine but also greatly improved its bioavailability.Remarkably,unlike other RXR? ligands,B-12 did not show side effects such as hypertriglyceridemia,hypercalcemia and hypercholesterolemia.The above results show that B-12 is a novel drug with stronger binding ability to RXR?,better anticancer effect,higher bioavailability and low toxicity and tumor selectivity,which has potential drug development value.In summary,our current research not only explores the molecular mechanism of berberine's inhibition of colon cancer cell proliferation through RXR?,but also describes a new effective anti-tumor drug method by reasonably designing the RXRa activator from berberine.It provides lead compounds for the development of new anti-colon cancer drugs targeting RXRa and presents new ideas for screening novel antitumor drugs with high biological activity.