榄香烯增敏蛋白酶体抑制剂硼替佐米抗胰腺癌的作用及其分子机制研究

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. The current chemotherapy for pancreatic cancer has limited efficacy and severe side effects. Therefore, it is of a high priority to develop effective therapeutic drugs for this malignancy. Elemene extracted from the Chinese herb Curcuma wenyujin, has been approved to treat a wide spectrum of cancers with fewer side effects. Experimental and clinical studies have demonstrated that elemene not only induces anti-cancer activities in multiple tumors, but also enhances the effects of chemotherapy or radiotherapy, or even potentially reverses the chemo-resistance of oncology drugs. The potential therapeutic effects of elemene combined with oncology drugs have not been studied on pancreatic cancer. For this purpose, we performed high-throughput screening of approved oncology drug library to identify which drug works synergistically with elemene on pancreatic cancer. Screening data indicates that elemene significantly enhances the cytotoxicity of bortezomib, a proteasome inhibitor on pancreatic cancer cells. In light of this discovery, the proposed investigation is intended to extensively study the combined effects of elemene and bortezomib on the proliferation and apoptosis of pancreatic cancer cells, and to reveal the related mechanism of action by SPR, proteomic analysis and other approaches. The therapeutic effects of elemene in combination with bortezomib will be evaluated in orthotopic pancreatic tumor xenograft models. The mechanism underlying its synergistic effects between elemene and bortezomib revealed in this investigation may provide valuable insights on elemene’s exact role in anti-cancer therapy and the potential application of elemene combined with bortezomib in pancreatic cancer treatment.

胰腺癌早期诊断困难、缺乏有效的治疗手段、死亡率极高，因此被称为“癌中之王”。现有化疗药物疗效欠佳且毒副作用大，亟需开发新的治疗手段。榄香烯是从中药温郁金中提取的广谱低毒抗癌新药，不仅可以治疗多种恶性肿瘤而且能增强放化疗的敏感性甚至逆转耐药，但是榄香烯联合抗肿瘤药物治疗胰腺癌并没有得到系统研究。因此我们对已批准的抗肿瘤药物库进行了榄香烯联合用药的高通量筛选，发现榄香烯可显著增强蛋白酶体抑制剂硼替佐米对胰腺癌细胞增殖的抑制，对死亡率极高的胰腺癌具有重要的价值。本项目旨在研究榄香烯联合硼替佐米在抑制胰腺癌细胞增殖及诱导细胞凋亡上的影响，采用表面等离子共振及蛋白组学等手段探讨榄香烯增敏硼替佐米抗胰腺癌的作用靶标及分子机制，并在人胰腺癌裸鼠移植瘤模型上验证二者联合用药的疗效。榄香烯与硼替佐米协同作用机制的阐明将为明确榄香烯在抗癌治疗中的作用提供有用信息，并为它们在胰腺癌上的可能应用提供科学依据。

胰腺癌早期诊断困难、缺乏有效的治疗手段、死亡率极高，因此被称为“癌中之王”。在过去40年中，其5年生存率不足10%。现有化疗药物疗效欠佳且毒副作用大，因此迫切需要开发更加安全有效的治疗药物。榄香烯是一种从中药温郁金（温莪术）中提取的小分子抗癌药物，不仅具有广谱抗癌功效，而且在增敏放化疗和逆转耐药方面有较多报道。为了系统寻找与榄香烯协同抗胰腺癌的药物，我们通过高通量筛选的方法对已批准的抗癌药物进行榄香烯联合用药的筛选，发现榄香烯可显著增强硼替佐米对胰腺癌细胞增殖的抑制。硼替佐米作为一种批准用于治疗多发性骨髓瘤和套细胞淋巴瘤的蛋白酶体抑制剂药物，它与榄香烯联用具有显著的协同增效抗胰腺癌的作用。在胰腺癌细胞上，榄香烯的加入明显增强硼替佐米对胰腺癌细胞的增殖抑制、周期阻滞及诱导凋亡作用。在裸鼠移植瘤模型中，相较单药组二者联用具有更好的抑制肿瘤效果。计算模拟分析及实验研究发现，榄香烯与20S蛋白酶体的活性位点稳定结合，这重塑了抑制剂结合区的几何形状和生物特性。榄香烯的这种“分子补丁”作用对硼替佐米的结合更有利，增强了硼替佐米对蛋白酶体的抑制作用，从而极大提高了硼替佐米的细胞毒作用和抗肿瘤效果。此外，蛋白组学分析及关键差异蛋白的验证，也证实了榄香烯与硼替佐米通过抑制蛋白酶体介导的下游细胞周期和凋亡调节因子这一通路发挥协同抗肿瘤作用。这项工作首次证明了榄香烯联合硼替佐米治疗胰腺癌的潜在价值，值得在临床前和临床研究中进一步评价其有效性和安全性。提出的“分子补丁”机制对于理解、优化甚至最终设计基于分子补丁的小分子药物提供了思路。