Preliminary Study On Molecular Mechanism Of Anti-Osteosarcoma Effects Of Novel Diamino Ester Compounds

Osteosarcoma is one of the most common malignant bone tumors,which occurs in adolescents aged 10-30 years,but it can occur at any age.Owing to its insensitivity to chemotherapeutics and easy to metastasis and recurrence,the survival rate of osteosarcoma patients is generally low.Therefore,it’s very urgent to find the target and corresponding therapeutic drugs for osteosarcoma.Previous studies have found that LR4,a new diaminoester compound,has good anti-tumor activity.The IC₅₀ values of all the tested tumor cells were at the hundreds of namonanomore or micromolar level,and LR4 had the best activity against osteosarcoma cell SJSA-1,with the IC₅₀ value of 67.9 nM.It can induce apoptosis of osteosarcoma cells（SJSA-1）,decrease mitochondrial membrane potential and ATP production,and inhibit the activation of NF-kappa B pathway and AKT protein.Therefore,we chose two kinds of osteosarcoma cells as the research objects,further tested the anti-osteosarcoma activity of LR4 in vitro and in vivo,and then preliminarily studied the molecular mechanism of LR4 by using molecular biology.We found that LR4 could induce apoptosis in the presence of Caspase inhibitor Z-VAD-FMK,It can also up-regulate the expression of AIF,promote the entry of AIF into the nucleus,and up-regulate p53.However,the interaction between the two osteosarcoma cells and XIAP shows opposite results,Therefore,there may be different anti-tumor mechanisms in the two kinds of cells,and the specific mechanisms need to be studied.The results of mRNA sequencing showed that LR4induced differential expression of PI3K-AKT,VEGF,MAPK,IL-17 and TNF signaling pathway-related proteins.The abnormalities of these pathways may be related to the anti-osteosarcoma activity of LR4.This paper demonstrates that LR4,a new diaminoester compound,plays an anti-osteosarcoma role through Caspase-independent programmed death pathway and has certain activity in vivo and in vitro.It is expected to become a new lead compound for anti-osteosarcoma and provide new research ideas and targets for the treatment of osteosarcoma.