HDAC和HMGCR抑制劑在大腸直腸癌之研究

Abstract

大腸直腸癌為全球發生率第三之癌症，遠端轉移為致死主因，轉移性大腸直腸癌為無法治癒之疾病，標靶藥物合併化學治療可延長病患存活時間，為目前轉移性大腸直腸癌之治療準則，因此，研發新藥以延長病患存活時間為目前研究之重要方向。我們研發JMF compound為抑制HMGCR和HDAC活性之小分子藥物，實驗發現hydroxymate group binding HDAC之抑制效果最佳，JMF3086與金屬離子結合於缺氧環境可釋放JMF3086單體，抑制xenograft動物模式腫瘤;抑制大腸直腸癌之肝臟轉移中，JMF3086與化療藥物irinotecan合併使用具加成性，顯示JMF3086為極具潛力之抗癌藥物。HMGCR於癌症中有過度表現之現象，但其扮演角色仍不清楚，我們發現HMGCR之過度表現可促進腫瘤細胞之存活，並增加COX-2和DNMT蛋白之表現;反之，抑制HMGCR則促進細胞凋亡，顯示HMGCR於腫瘤細胞中扮演促進腫瘤生長之角色，是癌症治療之標的。

Colorectal cancer (CRC) is the third most common cancer in the world and metastases are the main cause of death in CRC. Metastatic CRC is incurable, discovery of new chemotherapeutic and molecular target angents prolongs the survival of metastatic CRC, implying the necessity of new drug development. We designed the dual-function anticancer agent to target both 3-hydroxy-3methylgutaryl CoA reductase (HMGCR) and histone deacetylase (HDAC). In this study, the hydroxymate-containing HDACi (JMF3086) exhibits most potency to inhibit the HDAC activity. JMF3086 metallo-complexes could release JMF3086, so that to inhibit tumor growth in CRC xenograft models. In spleen-liver metastasis model, JMF3086 showed synergistic effect with irinotecan in vivo, indicating JMF3086 as a potential anticancer agent. HMGCR is overexpressed in cancers, but how HMGCR interconnects with oncogenic signaling are still unclear. We found that overexpression of HMGCR could promote cell growth and induce the expressions of COX-2 and DNMT in CRC cells. On the contrary, knockdown of HMGCR could promote apoptosis. These results indicated HMGCR plays an important role in tumor growth, and HMGCR can be a therapeutic target for cancer treatment.