Study On The Inhibition Of Tumor Growth In Breast Cancer By BCL-2 BH4 Domain Antagonist

Breast cancer is a common malignant tumor in female.In China,the incidence of breast cancer is the highest of female cancer,the mortality rate is second to lung cancer.The BCL-2 gene has anti-apoptotic effect,breast cancer cells with high expression of BCL-2 have obvious tolerance to radiotherapy and chemotherapy drugs.Apoptosis pathway related drugs combined with adjuvant therapy are used to increase the sensitivity of breast cancer patients to radiotherapy and chemotherapy.Thus,BCL-2 may be a therapeutic target of breast cancer.Targeted drug research and development of the BCL-2 has been widely concerned.The BCL-2 protein is composed by four conservative BCL-2 homologous structure domain(BH1~BH4).BH3 domain as a key domain to pro-apoptosis,prompting the BCL-2 family proteins form a homologous dipolymer performs the function of apoptosis;BH4 domain covers the BH3 structure to inhibit pro-apoptosis.Thus,BH4 domain plays a crucial role to anti-apoptotic function.However,the treatment of single targeted apoptotic pathways drug,which is designed by BCL-2 family BH3 domain is not ideal.Therefore,if we can develop a small molecule compounds which against the functions of BH4 domain,and translates BCL-2 from anti-apoptotic molecules into pro-apoptotic factors,it will provide novel ways for targeted therapy of breast cancer.Tumor is normal cells which are stimulated by carcinogenic factors,results in tumor cells grow rapidly,unlimited proliferation and form into neoplasms.New blood vessels to provide nutrients for the growth of tumor,and provides channels for the distal metastasis of tumor cells,the lack of new blood vessels of the tumor will die because of its metabolic load.Tumor angiogenesis plays a crucial role in the process of the growth and metastasis of breast cancer.At present,single using targeted agents of tumor angiogenesis or tumor growth for the treatment of tumor did not achieve an ideal effect.Therefore,treatment of combination with targeting angiogenesis drugs and chemotherapy drugs were used in clinic of primary breast tumors.However,combination although obtained the good curative effect,it has increased the financial burden of patients.In this study,we preliminarily study the function of BCL-2 BH4 domain antagonist CYD0281.Confirmed that CYD0281 can against the BH4 domain of BCL-2 and inhibit its anti-apoptosis through expose BH3 domain,then converse BCL-2 to a pro-apoptotic death protein.This study use chicken embryos xenograft model,subcutaneous xenograft model in mice,confirm CYD0281 inhibition of tumor growth,and use chicken embryo villus allantois membrane(CAM)model,yolk sac membrane(YSM)model,matrigel plug model,model of rat arterial ring angiogenesis,vascular endothelial cells into tube formation and migration experiment,determine CYD0281 inhibition of angiogenesis.This study demonstrated that CYD0281 exposed BH3 domain structure by exposing the BCL-2 BH3 domain,promoted the vascular endothelial cells and breast cancer cells apoptosis,which cause inhibiting tumor angiogenesis and tumor growth,providing theoretical basis and the new strategy for targeted the development of anti-breast cancer drug.