Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong 518055, China; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, Guangdong 518060, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong 518055, China.
Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong 518055, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518060, China.
Drug Resist Updat. 2023 Nov;71:101005. doi: 10.1016/j.drup.2023.101005. Epub 2023 Aug 21.
AIMS: Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. METHODS: The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo. RESULTS: CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. CONCLUSIONS: Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.
目的：胰腺癌的多药耐药性是临床治疗中的一个重大挑战。蟾毒灵（BA）是从蟾蜍腺体分泌物中发现的一种化合物，可能有助于克服这一问题。然而，迄今为止严重的心脏毒性阻碍了其临床应用。因此，本研究旨在开发一种细胞膜伪装的 BA 负载的聚乳酸-共-羟基乙酸纳米颗粒（CBAP），并评估其在胰腺癌化疗耐药中的潜在作用。
方法：通过心电图、体重、不适评分和小鼠筑巢行为评估 CBAP 的毒性。此外，还在体外和体内研究了抗癌活性及其潜在机制。
结果：CBAP 显著减轻了 BA 介导的急性心脏毒性，并增强了胰腺癌对几种临床药物的敏感性，如吉西他滨、5-氟尿嘧啶和 FOLFIRINOX。机制上，CBAP 直接与核苷酸结合寡聚化结构域蛋白 2（NOD2）结合，并抑制核因子κB 轻链增强子的活化 B 细胞。这抑制了 ABC 转运蛋白的表达，ABC 转运蛋白负责癌细胞的化疗耐药性。
结论：我们的研究结果表明，CBAP 可直接抑制 NOD2。将 CBAP 与标准护理化疗药物联合使用是治疗胰腺癌的一种安全有效的策略。
Drug Resist Updat. 2023-11
Cochrane Database Syst Rev. 2018-2-6
Cochrane Database Syst Rev. 2024-12-5
Genes Dis. 2024-12-24
Mol Cancer. 2025-1-21
Zotero 插件