State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR).
Department of Nephrology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, P. R. China.
Phytomedicine. 2020 Dec;79:153342. doi: 10.1016/j.phymed.2020.153342. Epub 2020 Sep 10.
Multidrug resistance (MDR) is the major barrier to the successful treatment of chemotherapy. Compounds from nature products working as MDR sensitizers provided new treatment strategies for chemo-resistant cancers patients.
We investigated the reversal effects of nuciferine (NF), an alkaloid from Nelumbo nucifera and Nymphaea caerulea, on the paclitaxel (PTX) resistance ABCB1-overexpressing cancer in vitro and in vivo, and explored the underlying mechanism by evaluating drug sensitivity, cell cycle perturbations, intracellular accumulation, function and protein expression of efflux transporters as well as molecular signaling involved in governing transporters expression and development of MDR in cancer.
NF overcomes the resistance of chemotherapeutic agents included PTX, doxorubicin (DOX), docetaxel, and daunorubicin to HCT-8/T and A549/T cancer cells. Notably, NF suppressed the colony formation of MDR cells in vitro and the tumor growth in A549/T xenograft mice in vivo, which demonstrated a very strong synergetic cytotoxic effect between NF and PTX as combination index (CI) (CI<0.1) indicated. Furthermore, NF increased the intracellular accumulation of P-gp substrates included DOX and Rho123 in the MDR cells and inhibited verapamil-stimulated ATPase activity. Mechanistically, inhibition of PI3K/AKT/ERK pathways by NF suppressed the activation of Nrf2 and HIF-1α, and further reduced the expression of P-gp and BCRP, contributing to the sensitizing effects of NF against MDR in cancer.
This novel finding provides a promising treatment strategy for overcoming MDR and improving the efficiency of chemotherapy by using a multiple-targets MDR sensitizer NF.
多药耐药（MDR）是化疗成功治疗的主要障碍。天然产物化合物作为 MDR 敏化剂提供了新的治疗策略，用于治疗化疗耐药的癌症患者。
我们研究了来自荷叶和睡莲的生物碱烟碱（NF）对紫杉醇（PTX）耐药 ABCB1 过表达的癌症在体外和体内的逆转作用，并通过评估药物敏感性、细胞周期扰动、细胞内积累、功能和转运蛋白的蛋白表达以及涉及调节转运蛋白表达和癌症 MDR 发展的分子信号，探讨了其潜在机制。
NF 克服了包括紫杉醇、多柔比星（DOX）、多西他赛和柔红霉素在内的化疗药物对 HCT-8/T 和 A549/T 癌细胞的耐药性。值得注意的是，NF 抑制了 MDR 细胞在体外的集落形成和 A549/T 异种移植小鼠体内的肿瘤生长，这表明 NF 与 PTX 之间具有非常强的协同细胞毒性作用，组合指数（CI）（CI<0.1）表明。此外，NF 增加了 P-糖蛋白底物包括 DOX 和 Rho123 在 MDR 细胞中的细胞内积累，并抑制维拉帕米刺激的 ATP 酶活性。在机制上，NF 通过抑制 PI3K/AKT/ERK 通路抑制了 Nrf2 和 HIF-1α 的激活，进一步降低了 P-糖蛋白和 BCRP 的表达，这有助于 NF 对癌症 MDR 的敏化作用。
这项新发现为克服 MDR 和提高化疗效率提供了一种有前途的治疗策略，方法是使用多靶点 MDR 敏化剂 NF。
