The Anti-osteosarcoma Effects Of Thiazolones And The Preliminary Study Of MYOF On The Proliferation And Migration Of Osteosarcoma Cells

Osteosarcoma is a rare and lethal malignancy that commonly occurs in children and adolescent.At present,surgical amputation and adjuvant chemotherapy are the main treatments,while patients with unresectable metastatic osteosarcoma have an extremely poor prognosis.Because of many different subtypes and unknown mechanisms of tumorgenesis,the targets of osteosarcoma are still unclear.What is more,there is still no effective targeted therapy until now.Therefore,screening active compounds,discovering new anti-osteosarcoma targets and developing novel therapeutic agents are urgently in demand.In this paper,we screened out a series of novel thiazolones compounds that have excellent anti-osteosarcoma activity.Besides,we performed a preliminary evaluation of in vivo efficacy,pharmacokinetic activity,and safety of the most effective compound.And a preliminary study on their mechanism and targets were also carried out.We used CCK8 method to detect the anti-osteosarcoma cell activity of a series of novel thiazolone compounds.The results showed that the IC₅₀ values of these compounds were at the nanomolar level.Among them,the IC₅₀ of DYQ-90 was 19.33n M,which showed the most excellent activity.According to the structure of the compound,liver particle and pharmacokinetic data,DYQ-（R）-90 compound was selected to detect its anti-osteosarcoma activity in vitro,mechanism and target in MNNG/HOS cells.The results showed that DYQ-（R）-90 has good anti-osteosarcoma activity in vivo and in vitro,could induce G0/G1 phase arrest of the cell cycle,but hardly causes apoptosis and necroptosis.Since DYQ-（R）-90 has similar structure to compounds that target to MYOF according to literatures,we speculated that the target might be MYOF.Therefore,the anti-proliferative activity of DYQ-（R）-90 in cell lines with different expression levels of MYOF was determined,while the results showed that the expression level of MYOF did not affect the anti-proliferative activity of the compound,indicating that the target may be not MYOF.Similarly,the anti-proliferative activity of DYQ-（R）-90 in SAOS-2 cells,which has no P53 gene,was comparable to other osteosarcoma cells.Hence DYQ-（R）-90 may not target P53.The target of this compound needs further study.Previous studies have shown that MYOF plays an important regulatory role in various tumors.In order to explore the role of MYOF in regulating the proliferation and migration of osteosarcoma cells,we constructed a MNNG/HOS cell line stably expressing sh MYOF and conducted a preliminary exploration of its effects on the cell phenotype.The results showed MYOF can inhibit the proliferation of osteosarcoma cells and promote the migration of osteosarcoma cells.Therefore,MYOF may play a regulatory role in the development of osteosarcoma.In summary,we found a new thiazolone compound DYQ-（R）-90 with good anti-osteosarcoma activity,and it can induce MNNG/HOS cell cycle arrest,while has no obvious effects on MNNG/HOS cell apoptosis and necroptosis.The target may not be MYOF and P53.The specific anti-tumor mechanism and exact target of DYQ-（R）-90need to be explored by further studies.The research conducted a preliminary exploration in the discovery of thiazolone anti-osteosarcoma compounds,provided a certain research basis for discovering new targets for osteosarcoma and developing effective targeted therapy drugs.