Study On The Mechanism Of Quinoline Derivative 10E Mediating The Vacuole-like Death Of Hepatocellular Carcinoma Cells

Since 2021,liver cancer has become the sixth most common malignant tumor and the third leading cause of cancer death in the world,and the incidence rate of liver cancer in China ranks first in the world.In the past ten years,the number of deaths due to liver cancer in China has increased year by year,the mortality rate has occupied the second place among the causes of cancer death.Due to the slow onset,most patients with Hepatocellular Carcinoma(HCC)have lost the opportunity for surgery when they were first diagnosed,so they mainly rely on systemic anti-tumor therapy.However,the results of systemic antitumor therapy are disappointing,and the median overall survival of patients with advanced HCC is still less than one year.Therefore,it is urgent to develop new and effective drugs targeting HCC to reduce the mortality.Quinoline compounds have the advantages of diverse pharmacological activities and convenient preparation,and are widely used in the development of clinical drugs.In recent years,their role in tumor treatment has also been widely discussed.Quinoline compounds exert anti-tumor effects through various mechanisms,such as mediating DNA damage by inhibiting the function of DNA topoisomerase,or attacking the growth regulation mechanism of tumors by inhibiting the activity of protein kinases,both of which can be effective of killing tumor cells,but the side effects are more serious.What is rarely mentioned is the role of quinoline compounds in the programmed death of tumor cells.Autophagy is a classic programmed death pathway,and the regulation of tumor growth has two sides.On the one hand,it can maintain and promote tumor growth,and on the other hand,it can promote the death of tumor cells by regulating apoptosis.Recently,more and more anticancer drugs are targeting the autophagy pathway.The quinoline derivative 10 E used in this study has been confirmed to have anti-hepatocarcinoma effects,which may be related to the autophagy pathway,but the specific mechanism of its inhibition of hepatocarcinoma is still unclear.This study verified the effect of 10 E on inhibiting the growth of hepatocellular carcinoma at the animal level.At the same time,it was found that 10 E mediated the death of hepatocellular carcinoma cells at the cellular level,accompanied by a specific cytoplasmic vacuolization.It is highly believed that vacuolization is through autophagy mediates key markers of programmed cell death in liver cancer cells.The nature of vacuolation was explored by locating key molecular markers at the subcellular level,preliminary definition of vacuole as autolysosome,and vacuolization is related to autophagy and endocytosis.Transcriptome sequencing results showed that 10 E could trigger up-regulation of gene expression in pathways such as mitophagy,DNA damage repair,and regulation of endoplasmic reticulum-related proteins in liver cancer cells.Combined with the identification of molecular biology experiments,it was verified that10 E can cause DNA damage,endoplasmic reticulum stress and mitochondrial damage in liver cancer cells,and these damages may be closely related to autophagy and apoptosis.In conclusion,quinoline derivative 10 E can effectively inhibit HCC,and has certain safety,and it is expected to be applied in clinical anti-liver cancer treatment.At the same time,the mechanism related to the new vacuolar-like death mode of tumor cells explored in this study is expected to provide evidence and hints for the subsequent development of anti-tumor drugs through this mechanism.