School of Pharmacy, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, PR China; Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China.
Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (900 Hospital of the Joint Logistics Team), Fuzhou 350025, PR China; School of Pharmacy, Fujian Medical University, Fuzhou 350122, PR China.
Int J Pharm. 2024 Apr 25;655:124028. doi: 10.1016/j.ijpharm.2024.124028. Epub 2024 Mar 20.
Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.
卵巢癌是一种严重威胁女性生命的恶性肿瘤，化疗是其主要的临床治疗手段。然而，化疗面临着产生多药耐药（MDR）的问题，主要是由于 P-糖蛋白（P-gp）诱导的药物外排，导致化疗药物在细胞内的积累减少。P-gp 介导的药物外排需要三磷酸腺苷（ATP）水解来提供能量。因此，调节能量代谢途径和抑制 ATP 产生可能是逆转 MDR 的一种潜在策略。在此，我们基于 PLGA-PEG 纳米平台开发了一种载有线粒体氧化磷酸化（OXPHOS）抑制剂阿托伐醌（ATO）、糖酵解抑制剂槲皮素（QUE）和化疗药物紫杉醇（PTX）的 PTX-ATO-QUE 纳米颗粒（PAQNPs），通过多种途径抑制能量代谢来逆转 MDR。机制上，PAQNPs 可以通过抑制线粒体复合物 III 和己糖激酶 II（HK II）的活性，有效抑制 A2780/Taxol 细胞的 OXPHOS 和糖酵解途径，从而降低肿瘤细胞内的细胞内 ATP 水平。能量耗竭可以有效抑制细胞增殖，降低 P-gp 活性，增加细胞内 PTX 的积累。此外，随着 PTX 积累，细胞内活性氧（ROS）增加，导致化疗耐药细胞凋亡。此外，PAQNPs 显著抑制了 A2780/Taxol 荷瘤 NCG 小鼠模型中的肿瘤生长。肿瘤组织的免疫组织化学（IHC）分析显示 P-gp 表达受到抑制，表明 PAQNPs 通过诱导能量耗竭有效逆转肿瘤中的 MDR。此外，包括血液生化指标、主要器官重量和 H&E 染色图像在内的安全性研究结果表明，PAQNPs 具有良好的体内安全性。综上所述，结果表明，联合抑制 OXPHOS 和糖酵解两条能量通路可以增强化疗效果，逆转卵巢癌的 MDR。
