Decitabine Enhances The Anti-HCC Activity Of Lenvatinib By Affecting Caspase-related Proteins

[Purpose] Hepatocellular carcinoma(HCC)occurs in the most common malignant tumor of the liver,with a hidden onset and rapid progression.However,most patients lose the chance of surgery because they are diagnsed in the late stages of the disease.Although the targeted drugs such as sorafenib and lenvatinib have opened the door for molecular targeted treatment of advanced HCC and brought good news to patients,the use of toxic side effects and the emergence of drug resistance in clinical application are inevitable.Also,the limited survival time,the unclear improvement of symptoms and the unpredictability of the development of HCC lead to limited treatment outcomes.We hope to explore the difference of anti-HCC activity and monotherapy in combination with lenvatinib and decitabine,a kind of demethylated drug,and the internal influence mechanism,so as to provide new diagnosis and treatment ideas for the clinical treatment of HCC and provide theoretical basis for the research and development of new drugs.[Methods] Hep3 B cells of logarithmic growth stage were inoculated subcutaneously into the right armpit of 5-week-old BALB / c-nu nude mice to establish the subcutaneous tumor model of nude mice.After tumorigenesis,they were randomly divided into four groups.They were given 200 μL /(20g·d)DMSO,0.5 mg /(kg·d)lenvatinib,5 mg /(kg·d)decitabine,0.5 mg /(kg·d)lenvatinib plus 5 mg /(kg·d)decitabine by gavage.The body weight,spirit and food intake of mice were observed daily.The tumor volume and the weight of nude mice were monitored.The expression of Ki-67 protein was detected by immunohistochemistry(IHC).The proliferation and apoptosis of each group were compared by HE and Tunel staining.We detected the protein level of cleaved caspase3/9and cleaved PARP by Western blotting.[Results] Both lenvatinib and decitabine were effective in inhibiting tumor growth.The inhibition effect on tumor growth of transplanted tumor was more obvious than that of single drug.Western Blotting showed that the expression of cleaved caspase3/9 and cleaved PARP were both up-regulated in the combined treatment group(p<0.05).According to the HE staining and Ki-67 score of tumor tissue,the combined drug group has the lowest proliferation ability but the strongest apoptosis ability(p<0.05).[Conclusions] Both lenvatinib and decitabine can inhibit the growth of HCC and the anti-tumor effect is more significant when the two drugs are used together.Decitabine can promote the anti-hepatocellular carcinoma activity of lenvatinib by up-regulating the expression of cleaved caspase3/9 and cleaved PARP proteins related to apoptosis.