Hunan Provincial Key Laboratory of Microbial Molecular Biology, State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, P. R. China.
Academician Workstation, Changsha Medical University, Changsha, 410219, P. R. China.
Small. 2022 Jan;18(3):e2104034. doi: 10.1002/smll.202104034. Epub 2021 Nov 11.
Discovering new drugs and improving action mechanisms is a promising strategy to overcome chemotherapy ineffectiveness caused by cancer cell apoptosis resistance. Natural products (like cyclic lipopeptides, CLPs) are potential sources of nonapoptotic cell death inducers and can form diverse supramolecular structures, closely relating to their bioactivities. Herein, it is found for the first time that fatty chain is the key to maintain self-assembled form and antitumor activity of microbial-derived amphiphilic CLP bacillomycin Lb (B-Lb). Compared with B-Lb analogues assemblies without antitumor activity, B-Lb supramolecular self-assemblies (including nanomicelles, nanofibers, giant micrometer rods) can be generated in a multilevel and cross-scale manner and served as a methuosis-like cell death inducer triggered by cytoplasmic vacuolation through macropinocytosis in MDA-MB-231-Luc and MCF-7 cells and in vivo tumor-bearing mice. This study will promote constructing of customized CLP micro-/nanostructures with multipurposes and functions, and boost designing of new antitumor drugs as nonapoptotic cell death modulators based on structure-activity relationship.
发现新的药物并改善作用机制是克服癌细胞凋亡抵抗导致化疗无效的一种有前途的策略。天然产物（如环状脂肽，CLPs）是潜在的非凋亡细胞死亡诱导剂来源，可以形成多种超分子结构，与它们的生物活性密切相关。本文首次发现，脂肪酸链是保持微生物来源的两亲性 CLP 杆菌霉素 Lb（B-Lb）自组装形式和抗肿瘤活性的关键。与没有抗肿瘤活性的 B-Lb 类似物组装体相比，B-Lb 超分子自组装体（包括纳米胶束、纳米纤维、巨大的微米棒）可以以多层次和跨尺度的方式生成，并作为一种通过巨胞饮作用导致细胞质空泡化的细胞坏死诱导剂，在 MDA-MB-231-Luc 和 MCF-7 细胞以及体内荷瘤小鼠中引发细胞坏死。本研究将促进具有多种用途和功能的定制 CLP 微/纳米结构的构建，并基于结构-活性关系推动新型非凋亡细胞死亡调节剂抗肿瘤药物的设计。
