新穎HDAC抑制劑抗大腸直腸癌機轉之探討

Abstract

大腸直腸癌已躍居國人發生率最高的癌症，目前以手術切除最為有效，藥物用於手術後之輔助及晚期治療，我們開發新穎抗癌藥物JMF compounds，可同時抑制HDAC及HMG Co-A還原酶的活性，在大腸直腸癌細胞可誘發apoptosis，亦可透過抑制Akt及活化ER stress而在大腸直腸癌細胞及azoxymethane (AOM)/dextran sulphate sodium (DSS)動物模式誘發autophagy。Atg5 knockdown可抑制JMF-1所誘發的autophagy，並增加JMF-1對細胞存活率之影響，表示JMF-1誘發的autophagy可能為autophagic cell death。抑制p53可減少JMF-1誘發之apoptosis，但增加autophagy；而抑制p21則是減少JMF-1誘發之apoptosis及autophagy，這些結果指出，JMF-1可能是透過誘發apoptosis及autophagic cell death抑制癌細胞的生長，極具潛力成為抗癌新藥。

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. Although anticancer agents for CRC have been grown in the past decade, the 5-year overall survival is still poor. Hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGRi, Statins) and Histone deacetylase inhibitors (HDACi) show promising anticancer activity in preclinical studies. Several dual-targeted inhibitors of HDAC and HMGR have been developed (JMF compound). In this study, we showed that JMF-1 inhibited the growth of CRC cells via induction of apoptosis. JMF-1 induced autophagy through downregulation of Akt and induction of ER stress. JMF-1 also induced autophagy in azoxymethane (AOM)/dextran sulphate sodium (DSS) animal model. Inhibition of autophagy reduced JMF-1-induced cytotoxicity, indicating that JMF-1 induced autophagic cell death. JMF-1 promoted p53 and p21 expression. Inhibition of p53 reduced JMF-1-induced apoptosis, but promoted autophagy. However, inhibition of p21 reduced JMF-1-induced apoptosis and autophagy. These findings demonstrated that JMF-1 exhibited anticancer effect via apoptosis and autophagic cell death, and may be a potential drug for the treatment of CRC.