Abstract
The polycomb group gene, EZH2, is highly expressed in advanced bladder cancer. Here we demonstrated that down-regulation of EZH2 in tumor tissues after neo-adjuvant chemotherapy correlated with good therapeutic response in advanced bladder cancer. We next developed a small molecule, NSC745885, derived from natural anthraquinone emodin, which down-regulated EZH2 via proteasome-mediated degradation. NSC745885 showed potent selective toxicity against multiple cancer cell lines but not normal cells. NSC745885 treatment overcame multiple-drug resistance and inhibited growth of resistant cancer cells. Over-expression of EZH2 in cancer cells attenuated effects of NSC745885, suggesting that down-regulation of EZH2 was responsible for growth inhibition of NSC745885. NSC745885 also suppressed tumor growth and down-regulated EZH2 in vivo. These results indicate that NSC7455889 suppresses bladder cancer by targeting EZH2.
Highlights
Over the past decade, more than 350 new agents have reported to be in clinical development for cancer and cancer-related indications
The baseline enhancer of zeste homolog 2 (EZH2) expression levels in bladder cancer tissues did not correlate with the therapeutic response to neo-adjuvant chemotherapy among the 12 patients (Fig. B)
The present study shows that the natural product derivative NSC745885 efficiently depletes EZH2, resulting in the inhibition of cell growth in various cancer cells
Summary
More than 350 new agents have reported to be in clinical development for cancer and cancer-related indications. The approval process is often burdened by many difficulties, which can be divided into two categories: i) the safety profile and therapeutic efficacy of the new agent to reflect its survival benefits, and ii) the failure to identify essential drug target(s) responsible for cancer biology [1]. The favored method is high throughput screen (HTS) of massive libraries of pure synthetic compounds [4], but the output has been quite low, with
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