Antitumor Effect Of Tyroserleutide On The Growth Of Human BEL-7402 Hepatocarcinoma And Exploration Of The Preliminary Mechanism

Tyroserleutide significantly prolonged the survival times of mice transplanted with the hepatocarcinoma H22, Tyroserleutide significantly inhibited the growth of HCC BEL-7402 transplanted in nude mice. The constituting amino acids mixture of tyroserleutide could not inhibit the growth of the human hepatocarcinoma BEL7402 implanted into nude mice. The tumor inhibitory effect of Tyroserleutide was related to its peptide structure, not to its amino acid constituents. In combined use with Adriamycin on BEL-7402 transplanted tumor, tyroserleutide increased the tolerance of mice to the side effects of Adriamycin, and enhanced anti-tumor effect of Adriamycin. Observations under light microscope and electron microscopy showed that tyroserleutide destroyed the structure of chromatin, damaged cell organelles in tumor cells, and induced apoptosis and necrosis in tumor cells.Human gene-chip analysis suggested that tyroserleutide might regulate gene expression of tumor cell through many pathways. Tyroserleutide inhibited the genes responsible for mitochondria respiratory chain and tumor cell proliferation, and signal transduction, as well as the oncogene/anti-oncogene expression. Observations under electron microscopy showed that tyroserleutide destroyed the structure of chromatin, damaged mitochondria and endoplasmic reticulum in tumor cells, overloaded intracellular calcium ion and induced apoptosis and necrosis in tumor cells. Further study confirmed that tyroserleutide decreased mitochondrial transmembrane potential in tumor cell, decreased the mRNA expression of genes related to mitochondrial respiratory chain such as NDUFA2,NDUFA10,NDUFS1, SUCLG1, and damaged functions of mitochondrial in tumor cell. Calreticulin is a type of calcium binding protein in endoplasmic reticulum, and plays an important role in calcium homeostasis regulation Tyroserleutide could increase the mRNA and protein expression of calreticulin in tumor cells, furthermore, impact the calcium homeostasis in cancer. So the calcium overloaded, damage of cellular membrane and organelles, necrosis and apoptosis were observed in tumor tissue of human hepatocarcinoma BEL-7402 implanted into nude mice. Tyroserleutide markedly decreased the proportion of S-phase cells and increased the proportion of G0/G1 cells, increased the apoptosis rate statistically significantly and induced the apoptosis of tumor cells. Tyroserleutide decreased the amount of proliferation tumor cells and induced the apoptosis of tumor cells. Tyroserleutide also increased the mRNA and protein expression of anti-oncogene PTEN,P21,P27, inhibited expression of oncogene AKT.