Epigenetic藥物增加化療藥物在大腸直腸癌療效之研究

Abstract

大腸直腸癌為全球發生率排名第三之癌症，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，標靶藥物加上複方化學治療可延長病患存活時間至2年以上，為目前轉移性大腸直腸癌之治療準則，如何增加藥物療效、克服抗藥性、及新藥開發以延長病患存活時間為目前研究之重要方向。我們所開發的JMF compound是一具HDAC inhibitor與Statin活性之小分子藥物，本實驗發現JMF與Oxaliplatin併用可經由促進細胞凋亡克服hypoxia下之抗藥性，具加成性抑制細胞之作用。利用Xenograft模式、大腸直腸癌肝轉移模式和AOM/DSS誘發之大腸直腸癌模式測試合併JMF與Oxaliplatin於動物模式之效果，合併用藥可加成性抑制腫瘤之生長，促進凋亡，降低腫瘤內HIF-1與VEGF之表現，更可增加E-cadherin及減少轉錄因子Slug之表現抑制EMT進行。以上結果顯示JMF是一極具潛力之抗癌藥物，可與現有化療藥物併用克服hypoxia引發之抗藥性並增加化療藥物對大腸直腸癌之療效。

Colorectal cancer is the third most common cancer in the world, metastases are the main cause of death in colorectal cancer. Metastatic colorectal cancer is incurable, target therapy combined with chemotherapy regimens increases patient median survival and has been the standard practice for metastatic colorectal cancer. Improve the efficacy of treatment for metastatic colorectal cancer, overcome drug resistance and drug development to prolong patient survival time are the main focus of medical research. We have designed and synthesized the JMF compound which is a dual inhibitor of HDAC and HMGR. In this study, we showed that JMF combined with Oxaliplatin can overcome hypoxia-induced resistance and synergistically inhibit cell proliferation in colorectal cancer cells . We used xenograft model、CRC metastasis to liver model and AOM/DSS induced CRC model to test the effect of JMF combined with Oxaliplatin in vivo. Combined therapy has synergistic effect of tumor inhibition in vivo, it induces apoptosis, decreases HIF-1 and VEGF expression, increases E-cadherin expression and decrease Slug expression to inhibit EMT. These findings demonstrate that JMF combined with chemotherapy as a promising strategy to colorectal cancer treatment can overcome hypoxia-induced drug resistance and improve therapeutic effects.