The Mechanism Of Effects On Infantile Hemangiomas Treated By DihydrotanshinoneⅠ

Background: Infantile hemangiomas(IH)is a common and benign vascular neoplasms with an estimated prevalence of 5–10%.The etiopathogenesis of IH have not been fully elucidated.Although majority of the IHs can spontaneous regress,some patients may be associated with complications resulting in pain,functional impairment,or permanent disfigurement.Treatment options of IH include corticosteroids,surgery,vincristine,interferon or cyclophosphamide,while none of therapeutic modalities are ideal due to restrictions or potential serious side effects.There is thus a need to explore novel treatments for IH.Plant-derived phytochemicals have been widely used as therapeutic agents for thousands of years in China.Herbal extracts are used commonly around the world for treating illness and improving health.Hemangiomas generally belong to “RouLiu” in traditional Chinese medicine,which are caused by obstruction of meridian and collateral,and are required to “activate blood circulation”.The dry root of S.miltiorrhiza,also called Tanshen,is widely used in traditional Chinese medicine for the effect of “active blood circulation”.In this study,we tested the effects of lipophilic tanshinones on EOMA cell function,and we identified DHTS as the most potently cytotoxic of the tanshinones examined.The results of our studies showed DHTS was the most potent cytotoxity of all tanshinones,which had ever been reported to have cytotoxicity and anti-angiogenesis to tumor cells.The same effect was also observed in the cells treated by propranolol,but with almost 20-fold of drug concentration as compared with DHTS.Our research may provide a foundation for the clinical development of DHTS as an alternative treatment for infantile hemangiomas.Methods: Cell viability,apoptosis,protein expression and anti-angiogenesis were analyzed by CCK8,Annexin V staining,Western blot and tube formation,respectively.The anti-tumor activity of DHTS in vivo was evaluated using a mouse xenograft model.We set propranolol as positive control group for the following experiment.Results: Fourteen major compounds extracting from tanshinones were screened for the inhibition of hemangiomas cells.Of these compounds,DHTS showed the most potent inhibition effects on hemangioma cells.DHTS could significantly decrease EOMA cells proliferation by inducing cell apoptosis,which is much more efficient than propranolol in vitro.Apoptosis relevant proteins including PARP,AIF,Caspase9,Bax,Cyst3,FADDand Caspase8 were significantly regulated after DHTS treatment in EOMA cells.In addition,DHTS significantly inhibited tube formation in vitro by downregulating vascular endothelial cell growth factor receptor 2(VEGFR2)and matrix metalloproteinase 9(MMP9)expression.In nude mice xenograft experiment,DHTS(10mg/kg)could significantly inhibited the tumor growth of EOMA cells as well as propranolol(40mg/kg).Conclusion: Our findings reveal for the first time that in vivo and in vitro,the anti-angiogenic and apoptosis-inducible activity of DHTS occur at significantly lower doses than propranolol,which could be potentially become a new and high effective compound for the treatment of infantile hemangiomas.