The Mechanism Study Of Small Molecular Compounds On Leukemia

Acute myelogenous leukemia(AML) is a highly heterogeneous group of hematopoietic diseases which is characterized by accumulation of myeloid leukemia blasts originated from the malignant hematopoietic stem/progenitor cells. AML accounts for about 25% of the adult leukemias and mainly develops in the elderly, with a growing incidence over 65 years. Although 70-80% of AML patients acquire complete remission after induction chemotherapy, most of them will relapse and die from the disease. Therefore, it is necessary to develop new drugs which are more effective and less toxic than traditional chemotherapeutic drugs for the treatment of AML. The aim of this research is to depict the mechanisms of two leading compounds which possess potential anti-AML activities.Cordycepin, an adenosine analog derived from Cordyceps militaris has been shown to possess anti-tumor activity in many ways. However, the mechanism by which cordycepin exerts effect on tumor cells should be further addressed. Here we show that cordycepin inhibits cell growth in NB4 and U937 cells by inducing apoptosis. Further study reveals that cordycepin increases the expression of p53 which promotes the release of cytochrome c from mitochondria to the cytosol. The released cytochrome c can then activate caspase-9 and trigger intrinsic apoptotic pathway. Cordycepin also blocks MAPK pathway by inhibiting the phosphorylation of ERK1/2, and thus sensitizes the cells to apoptosis. In addition, our results show that cordycepin inhibits the expression of cyclin A2, cyclin E and CDK2, which leads to the accumulation of cells in S-phase. Moreover, we show that cordycepin induces DNA damage and causes degradation of Cdc25 A, suggesting that cordycepin induced S-phase arrest involves activation of Chk2-Cdc25 A pathway. In conclusion, cordycepin-induced DNA damage initiates cell cycle arrest and apoptosis which then leads to the growth inhibition of NB4 and U937 cells.Marine-derived terpenoids possess novel carbon skeletons which are different from those present in terrestrial species. Many of them exhibit a wide variety of biological activities, such as anti-tumor, anti-inflammatory and antimicrobial effects. Sesterstatin 4 and 5 are scalarane sesterterpenoids which exhibit potent anti-tumor activities. In this study, the anti-leukemia activities of analogues of sesterstatin 4/5 and their intermediates are investigated. A group of compounds including ZEG-2, ZEG-10, ZEG-11, ZEG-14 and ZEG-15 have been found to effectively inhbit the growth of HL-60 cells. Further study showed that ZEG-14 and ZEG-15 can induce caspase-dependent apoptosis. ZEG-14 and ZEG-15 down-regulate the expression of cyclin A2, cyclin E, CDK2 and CDK4, and inhibit the phosphorylation of Rb, leading to the accumulation of cells in G0/G1 phase. In addition, our study show that ZEG-14 and ZEG-15 are capable of inducing DNA damage and activating ATM/ATR pathway, which leads to the degradation of Cdc25 A and subsequent silencing of the CDK2 and CDK4 activities. As a result, Rb cannot be phosphorylated and cell cycle arrest occurs. In conclusion, ZEG-14 and ZEG-15 exert inhibitory effects on the growth of HL-60 cells through induction of cell apoptosis and cell cycle arrest.