Mechanisms Of Breast Cancer Inhibition By Tiamulin And Prostate Cancer Prevention By δ-Tocopheral In Vivo

Background:Breast cancer is the most frequent cancer in women,as well as in bitches.Metastasis is the leading cause of death in breast cancer patients.CD73,also known as ecto-5’-nucleotidase,plays a vital role in cancer development including metastasis.The existing researches indicate that overexpression of CD73 promote growth and metastasis of breast cancer.Therefore,CD73-targeted inhibitor can offer a promising treatment for breast cancer.Here,we determined whether tiamulin,which was found to inhibit CD73,was able to suppress breast cancer development and the related mechanisms.Prostate cancer is one of the most common cancers in male.Tocopheral was reported to prevent various types of cancer,including prostate cancer,and δ-tocopheral was shown to decrease pAKT level in prostate cancer cell.We studied the prostate cancer preventive activity of δ-tocopheral using PTEN-/-mice.Methods:(1)The effect of tiamulin hydrogen fumarate(THF)on CD73 was determined by high performance liquid chromatography(HPLC).Then,the cell proliferation,migration and invasion were investigated in MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line treated with THF by migration assay,invasion assay and activity assay.(2)The effect of THF on allograft mammary tumors of mice was examined by tumor volume and weight measurement,and immunohistochemistry.(3)The effect of δ-tocopheral on prostate cancer in PTEN-/-mice was examined by histopathology and and immunohistochemistry.Results:(1)Our data demonstrated that THF inhibited CD73 by decreasing the activity instead of the expression of CD73.In vivo,THF inhibited the proliferation,migration and invasion of MDA-MB-231 and 4T1 cells by suppressing CD73 activity.(2)In vivo,allograft experiments showed that THF treatment resulted in significant reduction in allograft tumor growth,microvascular density and lung metastasis rate.(3)PTEN-/-mice model showed that δ-tocopheral reduced the level of pAKT and Ki67,and also decreasing the number of prostate glands containing adenocarcinoma.Conclusion:(1)Our results indicate that THF inhibit growth and metastasis of breast cancer by blocking the activity of CD73,which may offer a promising treatment for breast cancer therapy.(2)Our results indicate that δ-tocopheral prevent prostate cancer might by decreasing the level of pAKT.