Anti-tumor activity in vitro and in vivo from DNA damage induced by QS-ZYX-1-61

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore B43 Agents that cause DNA damage have been widely used as anticancer drugs for decades. The DNA lesions can make DNA checkpoints initiation and induce cell death. In recent years, there are many clinical trials were designed in combination with many DNA damage agents which trigger apoptosis through different mechanisms. The compound QS-ZYX-1-61 is a new DNA damage drug which GI50 value of 0.02 μM in A549 human lung carcinoma cells using SRB assay. We found that treatment with QS-ZYX-1-61 results in a dramatic increase of apoptosis with caspase- 3/8/9 activation and survivin down-regulation using Western blot analysis. In addition, the increased expressions of p53, p21, and Bcl-2 family member puma, indicated the cell cycle arrest at G1/S phase after the cells had been treated with QS-ZYX-1-61. However, both the ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with DNA damage agents. In the present data indicate that exposure to QS-ZYX-1-61 may lead to ATM and chk2 activation, with the downstream consequences related to the arrest in cell cycle progression to undergo apoptosis. In a corollary in vivo study, QS-ZYX-1-61 significantly inhibition of tumor growth in SCID mice inoculated with A549 cells. Taken together, our results indicate that QS-ZYX-1-61 induces cell cycle arrest and inhibits tumor growth in vitro and in vivo via the activation of DNA damage checkpoints in A549 cells. Base on these results, QS-ZYX-1-61 is a potential antitumor agent worthy of further investigation.