Pomiferin通过作用于 SERCA、mTOR 和 P-gp，诱导凋亡抵抗癌细胞进行自噬性细胞死亡，并且在体内逆转顺铂耐药肿瘤的多药耐药表型。
Pomiferin targets SERCA, mTOR, and P-gp to induce autophagic cell death in apoptosis-resistant cancer cells, and reverses the MDR phenotype in cisplatin-resistant tumors in vivo.
发表日期：2023 Apr 13
作者：
Yuan-Qing Qu, Lin-Lin Song, Su-Wei Xu, Margaret Sum Yee Yu, Onat Kadioglu, Francesco Michelangeli, Betty Yuen Kwan Law, Thomas Efferth, Christopher Wai-Kei Lam, Vincent Kam Wai Wong
来源：
PHARMACOLOGICAL RESEARCH
摘要：
癌症药物耐受性被分为先天性耐受性和获得性耐受性，其中先天性耐受性特征为凋亡缺陷，获得性耐受性具有ABC转运蛋白过度表达。因此，预防或逆转这些耐药机制可能是改善化疗结果的有前途的策略。在这项研究中，奥萨奇橙中的天然产物石斛酸被鉴定为一种新型自噬激活剂，通过抑制SERCA和激活CaMKKβ-AMPK-mTOR信号级联而促进自噬细胞死亡，从而避免先天性耐受性。此外，石斛酸还直接抑制P-gp（MDR1 / ABCB1）外流并通过增强化疗药物顺铂的积累和疗效来逆转获得性耐受性。体内研究表明，石斛酸触发了钙介导的肿瘤抑制，并在LLC-1肺癌携带的小鼠模型中表现出抗转移作用。此外，作为佐剂，石斛酸通过特异性抑制ABCB1介导的药物外流而不是ABCC5，从而促进顺铂在肿瘤中的积累，在RM-1耐药性前列腺癌携带的小鼠模型中增强了化疗药物顺铂的抗肿瘤效果。总之，石斛酸可能作为一种新型有效的药物在临床应用中用于避免药物耐药。Copyright © 2023. Published by Elsevier Ltd.
Drug resistance in cancer has been classified as innate resistance or acquired resistance, which were characterized by apoptotic defects and ABC transporters overexpression respectively. Therefore, to preclude or reverse these resistance mechanisms could be a promising strategy to improve chemotherapeutic outcomes. In this study, a natural product from Osage Orange, pomiferin, was identified as a novel autophagy activator that circumvents innate resistance by triggering autophagic cell death via SERCA inhibition and activation of the CaMKKβ-AMPK-mTOR signaling cascade. In addition, pomiferin also directly inhibited the P-gp (MDR1/ABCB1) efflux and reversed acquired resistance by potentiating the accumulation and efficacy of the chemotherapeutic agent, cisplatin. In vivo study demonstrated that pomiferin triggered calcium-mediated tumor suppression and exhibited an anti-metastatic effect in the LLC-1 lung cancer-bearing mouse model. Moreover, as an adjuvant, pomiferin potentiated the anti-tumor effect of the chemotherapeutic agent, cisplatin, in RM-1 drug-resistant prostate cancer-bearing mouse model by specially attenuating ABCB1-mediated drug efflux, but not ABCC5, thereby promoting the accumulation of cisplatin in tumors. Collectively, pomiferin may serve as a novel effective agent for circumventing drug resistance in clinical applications.Copyright © 2023. Published by Elsevier Ltd.