Studies On Anti-tumor Mechanism Of Gossypol Derivatives

Tumor cells are mutated from normal somatic cells and lose their normal regulation of growth.One of the most prominent features is immortality,continuous division and reproduction,specifically characterized by inhibition of the apoptotic pathway of tumor cells,and cell cycle.Out of control,not controlled by normal growth control systems.Therefore,in view of the infinite proliferation of cancer cells,finding the differences and blocking them from the normal pathways of apoptosis and cell cycle,and finding related targeted drugs are the main research directions of many researchers.Gossypol is a polyphenolic hydroxybisnaphthaldehyde derived from the roots and leaves of cotton.It is mainly used for male contraception.Studies have shown that it has antitumor activity,but it is more toxic.The toxicity is mainly due to the aldehyde group of the compound.By analyzing the structure of gossypol,we found that it can act on the active pocket of Bcl-2 family proteins.The up-or down-regulation of Bcl-2 family proteins such as Bcl-2,Mcl-1 and Bcl-x L is closely related to the development of cancer cells.Therefore,we designed and synthesized a series of gossypol derivatives targeting Bcl-2 family proteins based on fragment-based drug design(FDBB)and structureactivity relationship(SAR).Using fluorescence polarization technology,we screened in vitro protein levels.Several active small molecules.Subsequently,it was confirmed in cell experiments that it has a good inhibitory activity on tumor cells.To further verify the mechanism of the screening of gossypol derivatives to inhibit tumor cell growth,we performed active small molecules from in vitro and in vivo experiments,transcribed RNA levels,and protein levels.Studies have attempted to resolve the mechanism of action by adding changes in the apoptotic pathway and cell cycle before and after the addition of small molecules.This paper mainly involves screening two drug candidates,lyz-003-231 and DW-163.The EC50 of HCT-116 and NCI-H460 tumor cells is about 50 n M,which has obvious inhibitory effect on cancer cells..Through apoptosis experiments,it was found that 10%～15% of tumor cells undergo apoptosis under the action of lyz-003-231,and the cell cycle results indicate that lyz-003-231 can cause cell arrest in cell cycle G0/G1 phase.Causes tumor cells to continue to proliferate.DW-163 and lyz-003-231 have similar drug effects as described above,which cause 10% to 20% of apoptosis in apoptosis,and cell cycle experiments show that G0/G1 phase cell resistance is caused by low concentration.Hysteresis,high concentration directly causes DNA damage,leading to apoptosis.These two drug candidates promote apoptosis associated with the apoptosis-related protein PARP and the cell cycle-regulating protein Cyclin D1,and they also show the same results at the transcriptional level.Although the two drugs promote cancer cell apoptosis,the pathway is still not particularly clear,but in the later experiments,it will continue to explore its pathway to promote apoptosis,and to verify its effects in mammals in animal experiments.To provide a better experimental basis for its medicine.