Molecular Mechanism Of LJK-11, A Novel Synthetic Analog Of 5, 8-disubstituted Quinazolines, Induces Apoptosis Of Tumor Cells

Tyrosine kinase inhibitors and mitosis inhibitors are powerful anticancer drugs. Research and development of tyrosine kinase inhibitor and mitosis inhibitors have become a hotpot in the research area of anti-anticancer drugs. In this paper, by investigating the molecular effect mechanism of 5, 8-disubstituted quinazolines LJK-11 on cancer cells, we have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker and tyrosine kinase inhibitor.We found that LJK-11 could inhibit growth and induced apoptosis of many different types of tumor cells. LJK-11 inhibited phosphorylation of HER2, but inhibited hardly phosphorylation and expression of tyrosine kinase of AKT, JNK and Pyk2 that regulated proliferation, metabolism, immunoreaction of tumor cells.The immediate cause inducing of cell death was attributed to LJK-11's effect on the cell cycle. It prevented mitotic spindle formation and arrested cells at G2/M phase. In the presence of LJK-11, the chromosomes are unable to achieve bipolar attachment to the spindle and congress to the metaphase plate. The cells therefore remain blocked at prometaphase/metaphase of mitosis and eventually undergoes apoptosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. The mode of action of LJK-11 on microtubule polymerization resembles most closely that of colchicine.LJK-11 also had synergistic effect with colchicine on blocking cell mitosis. It however had neither synergistic nor additive effect with two other anti-microtubule agents, nocodazole or vinblastine. The effect of Colchicine on cell mitosis was irreversible, but the effect of LJK-11 was reversible. These data suggest that LJK-11 was different from colchicine.In conclusion, LJK-11 represents a novel anti-microtubule and tyrosine kinase-inhibited agent with therapeutic potential in treating cancer. Understanding of the mechanism of LJK-11 on induction apoptosis of tumor cells and its differences from other microtubule polymerization inhibitors will help us to design better anti-cancer drugs.