A novel mode of action of DNA alkylating anticancer agents

苯达莫司汀是一种抗淋巴瘤药物，最近在日本获得批准。尽管DNA被认为是该药物的主要靶点，但其作用机制的细节仍不清楚。在此，我们首次报道了本达对STAT3的抑制作用。在重组人STAT3蛋白的生化测定中，Benta显示了STAT3-SH2的拮抗活性，而非活性代谢物。此外，苯达抑制了人乳腺癌细胞株MDA-MB-463中STAT3的DNA结合和转录活性。使用本达类似物的竞争下拉分析表明，该试剂与细胞STAT3紧密结合。因此，这些结果提示该药的抗癌和免疫调节作用可能与其对STAT3的抑制作用有关。

Bendamustine (Benda) is an anti-lymphoma drug, which was recently approved in Japan. Although DNA has been believed to be primary target of this agent, the details of mechanism of action still remain unclear. We herein, for the first time, report STAT3 inhibition by Benda. The STAT3-SH2 antagonistic activity was shown by Benda but not by the inactive metabolites in the biochemical assay using recombinant human STAT3 protein. Furthermore, Benda suppressed both DNA-binding and transcriptional activity of STAT3 in the human breast cancer cell line MDA-MB-463. The competitive pull-down assay using the Benda analogs revealed that this agent tightly bound to cellular STAT3. Therefore, those results suggest that the previously reported anti-cancer and immunomodulation effects by this agent might be associated with its inhibitory effect on STAT3.