Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo
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Published on: January 16, 2015
Shou-Hung Tang1, Hsu-Shan Huang2, Hong-Ui Wu3
1Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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.
Insights
Down-regulating EZH2 (Enhancer of Zeste Homolog 2) shows promise in treating advanced bladder cancer. A new compound, NSC745885, effectively targets and reduces EZH2, inhibiting cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The polycomb group gene EZH2 is highly expressed in advanced bladder cancer.
- EZH2 plays a critical role in cancer progression and is a potential therapeutic target.
Purpose of the Study:
- To investigate the role of EZH2 in bladder cancer response to chemotherapy.
- To develop and evaluate a novel small molecule inhibitor of EZH2.
Main Methods:
- Assessed EZH2 expression in tumor tissues post-chemotherapy.
- Synthesized and characterized NSC745885, an emodin-derived compound targeting EZH2.
- Evaluated NSC745885's efficacy in vitro against cancer cell lines and in vivo tumor models.
- Investigated the mechanism of EZH2 downregulation by NSC745885.
Main Results:
- Down-regulation of EZH2 correlated with good therapeutic response in advanced bladder cancer.
- NSC745885 selectively induced toxicity in cancer cells, not normal cells, via proteasome-mediated EZH2 degradation.
- NSC745885 overcame multi-drug resistance and inhibited tumor growth in vivo.
- Over-expression of EZH2 diminished NSC745885's anti-cancer effects.
Conclusions:
- NSC745885 effectively suppresses bladder cancer by targeting EZH2.
- Targeting EZH2 with novel small molecules represents a promising therapeutic strategy for advanced bladder cancer.
