Meng Jun, Yu Zhixin, Chen Hongying, Yu Xin, Jiang Mengshi, Zeng Xin-An, You Jian
School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States.
Phytomedicine. 2022 Dec;107:154446. doi: 10.1016/j.phymed.2022.154446. Epub 2022 Sep 8.
Brucea javanica oil (BJO) is the active substance extracted from the dry and mature fruit of Brucea javanica. Its pharmaceutical preparation, BJO emulsion (BJOE), is one of the most widely studied traditional Chinese medicine preparations for the treatment of malignancy. However, the unrevealed anti-tumor mechanism immensely limits further development of BJOE.
In this study, we delved into the anti-tumor mechanism of commercial BJOE, including its influence on the tumor microenvironment (TME) and the treatment effect when combined with anti-programmed cell death protein-1 (PD-1) therapy.
The cytotoxicity of BJOE was tested in different cells in vitro, and a Förster resonance energy transfer system was also constructed to predict the release behavior of BJOE in vivo. Then, a B16 melanoma mouse model was used to explore the combination of BJOE and anti-mouse PD-1 antibody therapy. In addition, mass cytometry was used to test the impact of both drugs on the TME.
Out data revealed that BJOE did not directly kill tumor cells in vitro. However, BJOE was mainly released at the tumor site, converting an immunosuppressive TME into an immune-activated state, and its combination with anti-PD-1 therapy significantly inhibited the growth of melanoma and prolonged the survival time of the mice due to an increase in cytotoxic T lymph (CD8 T) and helper/inducible T lymph (CD4 T) cells in lymph nodes and tumors.
Our work explored the anti-tumor mechanism of commercial BJOE and the regulation of cytokines by BJOE when it was combined with anti-PD-1 therapy in vivo. The combination of these therapies could increase the numbers of CD4 T-cells, CD8 T-cells, and effective natural killer cells and the ratio of MI/M2 macrophages in tumor tissues, promoting inflammatory activity and enhancing the anti-tumor effect. This study provides a theoretical basis for advancing the modern development of traditional Chinese medicine preparations and stands as a reference for clinically improving the efficacy of PD-1 antibodies.
鸦胆子油（BJO）是从鸦胆子干燥成熟果实中提取的活性物质。其药物制剂鸦胆子油乳剂（BJOE）是治疗恶性肿瘤研究最为广泛的中药制剂之一。然而，未揭示的抗肿瘤机制极大地限制了BJOE的进一步发展。
在本研究中，我们深入探究市售BJOE的抗肿瘤机制，包括其对肿瘤微环境（TME）的影响以及与抗程序性细胞死亡蛋白1（PD-1）疗法联合使用时的治疗效果。
在体外不同细胞中测试BJOE的细胞毒性，并构建荧光共振能量转移系统以预测BJOE在体内的释放行为。然后，使用B16黑色素瘤小鼠模型探索BJOE与抗小鼠PD-1抗体疗法的联合使用。此外，采用质谱流式细胞术检测两种药物对TME的影响。
我们的数据显示，BJOE在体外不会直接杀死肿瘤细胞。然而，BJOE主要在肿瘤部位释放，将免疫抑制性TME转变为免疫激活状态，并且其与抗PD-1疗法联合使用可显著抑制黑色素瘤的生长并延长小鼠的存活时间，这是由于淋巴结和肿瘤中细胞毒性T淋巴细胞（CD8 T）和辅助/诱导性T淋巴细胞（CD4 T）数量增加所致。
我们的研究探索了市售BJOE的抗肿瘤机制以及BJOE在体内与抗PD-1疗法联合使用时对细胞因子的调节作用。这些疗法的联合使用可增加肿瘤组织中CD4 T细胞、CD8 T细胞和有效自然杀伤细胞的数量以及MI/M2巨噬细胞的比例，促进炎症活性并增强抗肿瘤效果。本研究为推进中药制剂的现代化发展提供了理论依据，并为临床上提高PD-1抗体的疗效提供了参考。
