Artesunate Suppresses The Growth Of Prostatic Cancer Cells Through Inhibiting Androgen Receptor

Prostatic cancer(PCa)is a leading cause of cancer related death in males and is often regarded as a kind of androgen-sensitive cancer.Androgen receptor(AR)is an important factor in progression of prostate cancer.Androgen deprivation therapy(ADT)is the standard treatment for prostate cancer,and can effectively inhibit tumor growth at early stage.After two or three years,the prostate cancer can recur or grow into castration-resistant prostate cancer(CRPC).Now there are many papers about mechanisms of the occurrence and development of CRPC after therapy of ADT,which in-clude change of the steroid hormone metabolism,AR gene amplification or express,AR co-regulators,AR splicing variants,growth factors and/or cytokines,AR mutation,etc.Now it is generally believed that androgen and androgen receptors play a key role in the devel-opment of CRPCArtesunate(ART),a semi-synthetic derivative of the Chinese herb artemisia annua,is such an anti-cancer agent.lt was proved to have anti-tumor effects.Such as anti-proliferative;induction of apoptosis;regulation of DNA methyltransderase enzymes and so on.Furthermore,the side effect is smaller than chemotherapeutics.lt can selectively kill cancer cells.However,the effects and mechanism of ART on PCa cells remains unclear.DNA methylation is a kind of genetic modification in human.DNA methyltransderase enzymes(DNMTs)are the most important regulator.The changes in the level of DNA methylation has important effect to the occurrence and development of tumor.The study aims to elaborate the mechanism of the involvement of androgen receptor(AR)in anti-prostatic cancer(PCa)of artesunate(ART).PCa cells 22rvl were used in vivo and in vitro,and the viability and apoptosis were conducted using MTT and TUNEL assay,respectively.Ectopic expressions of AR and DNA methyltransderase enzymes(DNMTs)were detected in cells in overexpression or interference of AR or DNMT3b.ART dose-dependently suppressed tumor growth,inhibited cell viability,enhanced apoptosis,decreased AR expression,and increased the expression and the catalytic activity of DNMT3b in 22rvl cells either in transplanted mice or in vitro.Furthermore,AR downregulated DNMT3b expression,and overexpression of AR or interference of DNMT3b could reverse ART-induced cytotoxicity and apoptosis in 22rvl cells,whereas overexpression of DNMT3b could not change the effect profiles of ART on the cells.The results indicated that ART suppressed tumor growth of prostatic cancer cells through AR-DNMT3b pathway,underlying ART will allow for the utilization of this Chinese therapeutic agent for the potential treatment of prostate cancer.