The release of anticancer drugs in systemic circulation and their associated toxicity are responsible for the poor efficacy of chemotherapy. Therefore, the identification of new chemotherapeutic combinations designed to be released near the tumor site in a sustained manner has the potential to enhance the efficacy and reduce the toxicity associated with chemotherapy. Here, we present the identification of a combination of doxorubicin, a DNA-binding topoisomerase inhibitor, with a naturally occurring triterpenoid, celastrol, that induces a synergistic effect on the apoptosis of colon cancer cells. Hydrogel-mediated sustained release of a combination of doxorubicin and celastrol in a murine tumor model abrogates tumor proliferation, and increases the median survival with enhanced apoptosis and concurrent reduction in proliferation. Sphingolipid profiling (LC-MS/MS) of treated tumors showed that the combination of celastrol and doxorubicin induces global changes in the expression of sphingolipids with an increase in levels of ceramides. We further demonstrate that this dual drug combination induces a significant increase in the expression of ceramide synthase 1, 4, and 6, thereby increasing the level of ceramides that contribute to the synergistic apoptotic effect. Therefore, hydrogel-mediated localized delivery of a combination of celastrol and doxorubicin provides a new therapeutic combination that induces a sphingolipid-mediated synergistic effect against colon cancer.

中文翻译：

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水杨酸和阿霉素的水凝胶介导的递送通过神经酰胺的上调诱导对肿瘤消退的协同作用。

全身循环中抗癌药物的释放及其相关毒性是造成化疗效果差的原因。因此，鉴定设计为以持续方式在肿瘤部位附近释放的新化学疗法组合具有增强疗效和降低与化学疗法相关的毒性的潜力。在这里，我们提出了阿霉素（DNA结合拓扑异构酶抑制剂）与天然三萜类化合物Celastrol的组合的鉴定，该三萜诱导对结肠癌细胞凋亡的协同作用。在小鼠肿瘤模型中，水凝胶介导的阿霉素和西司他特尔的组合的持续释放消除了肿瘤的增殖，并增加了中位存活率，同时细胞凋亡增加，增殖减少。经治疗的肿瘤的鞘脂谱分析（LC-MS / MS）显示，Celastrol和阿霉素的组合可诱导鞘脂表达的整体变化，并增加神经酰胺的水平。我们进一步证明这种双重药物组合诱导神经酰胺合酶1、4和6的表达显着增加，从而增加了有助于协同凋亡作用的神经酰胺的水平。因此，水凝胶介导的Celastrol和阿霉素的组合的局部递送提供了新的治疗组合，其诱导鞘脂介导的针对结肠癌的协同作用。我们进一步证明这种双重药物组合诱导神经酰胺合酶1、4和6的表达显着增加，从而增加了有助于协同凋亡作用的神经酰胺的水平。因此，水凝胶介导的Celastrol和阿霉素的组合的局部递送提供了新的治疗组合，其诱导鞘脂介导的针对结肠癌的协同作用。我们进一步证明这种双重药物组合诱导神经酰胺合酶1、4和6的表达显着增加，从而增加了有助于协同凋亡作用的神经酰胺的水平。因此，水凝胶介导的Celastrol和阿霉素的组合的局部递送提供了新的治疗组合，其诱导鞘脂介导的针对结肠癌的协同作用。