Citral is a widely used penetration enhancer that has been used to assist the delivery of drugs through the skin. In this study we aimed to investigate the effectiveness of combination treatments of citral with hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer and to unravel the underlying mechanism by which citral increased the efficacy of HIPEC. In vitro experiments indicated that citral increased cytoplasmic absorption of pirarubicin and potentiated the effects of pirarubicin on colorectal cancer cells to induce apoptosis. Intracellular reactive oxygen species (ROS) activity was elevated after single or combo treatments with pirarubicin, leading to compromised NF-κB signaling. Therefore, the results suggested that the effects of citral were mediated by increasing cell permeability and ROS productions. Furthermore, the colorectal xenograft model was used to evaluate the efficacy of the combo treatment at the histological and molecular levels, which showed that the cotreatment with citral for colorectal cancer increased the efficacy of HIPEC with pirarubicin with respect to both ascite control and tumor load. The results indicated that citral was an effective additive for HIPEC with pirarubicin for colorectal cancer, which warrant further effort to explore the translational application of this new treatment regimen.

中文翻译：

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柠檬酸的联合治疗增强了高温腹腔化学灌注与吡柔比星治疗结直肠癌的疗效

柠檬醛是广泛使用的渗透促进剂，已用于辅助药物通过皮肤的输送。在这项研究中，我们旨在研究柠檬醛与高温腹膜内化疗（HIPEC）联合治疗结直肠癌的有效性，并揭示柠檬醛增加HIPEC疗效的潜在机制。体外实验表明，柠檬醛可增加吡柔比星的细胞质吸收，并增强吡柔比星对大肠癌细胞的诱导凋亡作用。吡柔比星单次或联合治疗后，细胞内活性氧（ROS）活性升高，导致NF-κB信号转导受损。因此，结果表明柠檬醛的作用是通过增加细胞通透性和产生ROS来介导的。此外，使用结直肠异种移植模型在组织学和分子水平上评估了联合治疗的功效，这表明与柠檬醛共同治疗结直肠癌在腹水控制和肿瘤负荷方面均提高了HIPEC与吡柔比星的功效。