CUDC-101增强吉西他滨抑制胰腺癌的作用及机制研究

Pancreatic Cancer is a kind of alimentary canal tumor with high mortality and poor prognosis. At present, gemcitabine is one of first-line drugs of defense against tumors, especially pancreatic cancer. But pancreatic cancer was found to be highly drug-resistant to gemcitabine, so prognosis of pancreatic cancer patients may not be significantly improved. The overexpression of HDAC (Histone deacetylase) caused imbalance of acetylation, and tumor formation. HDAC inhibitors can induce tumor cell differentiation, cycle arrest and apoptosis, which inhibit tumor growth. With the deepening of the study, more and more new HDAC inhibitors have been emerged. CUDC-101 was a multi-targeted HDAC inhibitor, which can against various tumor cells more significantly through inhibiting cell proliferation. It mainly targeted at HDAC, EGFR and HER2, and these targets are currently recognized as very important targets of tumor therapy. Our previous study showed that CUDC-101 can enhance the growth inhibition of pancreatic cancer induced by gemcitabine, but the mechanism is still not clear. This project, by using transwell, western blot, real-time PCR, other molecular biology techniques and animal experiments, will clarify the synergistic inhibitory effect and molecular mechanisms of CUDC-101 combination treatment with gemcitabine in pancreatic cancer. In addition, it will provide a possible new choice for clinical targeted therapy of pancreatic cancer.

胰腺癌是一种恶性度极高、预后差的的肿瘤。目前，吉西他滨是治疗胰腺癌的一线化疗药物之一，但对胰腺存在高度先天性和获得性耐药，不能明显改善患者的预后。组蛋白去乙酰化酶表达过度造成乙酰化的失衡会形成肿瘤，而HDAC抑制剂可诱导肿瘤细胞分化、周期停滞和凋亡，从而抑制肿瘤的生成。目前，新的组蛋白去乙酰化酶抑制剂相继出现，CUDC-101作为HDAC的新型多靶点抑制剂对多种肿瘤细胞具有较显著的抗增殖活性，主要作用于HDAC、EGFR和HER2等靶点，而这些靶点是目前公认的、非常重要的肿瘤治疗靶点。我们的前期研究发现CUDC-101与吉西他滨联合用药时可增强吉西他滨抑制胰腺癌的作用，但其机制尚不明确。本项目设计采用侵袭小室、蛋白印迹、Real time PCR等分子生物学技术与动物实验，研究CUDC-101和吉西他滨联合用药对胰腺癌的抑制作用及分子机制，为胰腺癌的临床靶向治疗提供可能的新选择。

胰腺癌是一种恶性度极高、预后差的的肿瘤。目前，吉西他滨是治疗胰腺癌的一线化疗药物之一，但对胰腺存在高度先天性和获得性耐药，不能明显改善患者的预后。CUDC-101作为HDAC的新型多靶点抑制剂对多种肿瘤细胞具有较显著的抗增殖活性，主要作用于HDAC、EGFR和HER2等靶点，而这些靶点是目前公认的、非常重要的肿瘤治疗靶点。我们的研究证明，CUDC-101通过诱导凋亡、抑制细胞增殖和EMT过程，增强了吉西他滨的抗肿瘤作用。我们认为CUDC-101联合吉西他滨不仅通过PI3K/mTOR信号诱导细胞凋亡，而且通过Erk信号降低PC对吉西他滨的敏感性。这些结果可能为PC的化疗联合治疗策略提供潜在的合理依据。