title: Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis.
abstract: Marine natural products are served as attractive source of anticancer therapeutics, with the great success of "first-in-class" drugs, such as Yondelis, Halaven, and Brentuximab vendotin. Lagunamides A-C from marine cyanobacterium, Lyngbya majuscula, exhibit exquisite growth inhibitory activities against cancer cells. In this study, we have systematically investigated the structure-activity relationships (SARs) of a concise collection of lagunamide A and its analogues constructed by total chemical synthesis against a broad panel of cancer cells derived from various tissues or organs, including A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60, and A375. The R configuration of lagunamide A at C-39 position was found to be the structure determinant for anticancer activity. Further molecular mechanism study in A549 cells revealed that lagunamide A induced caspase-mediated mitochondrial apoptosis. Accompanied with the dissipation of mitochondrial membrane potential (Δφm) and overproduction of reactive oxygen species (ROS), lagunamide A led to mitochondrial dysfunction and finally caused cell death. Moreover, both anti- and pro-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins participated in lagunamide A-induced mitochondrial apoptosis, especially myeloid cell leukemia-1 (Mcl-1). Overexpression of Mcl-1 partly rescued A549 cells from lagunamide A-induced apoptosis. This study suggests that lagunamide A may exert anticancer property through mitochondrial apoptosis. Together, our findings would provide insightful information for the design of new anticancer drugs derived from lagunamides.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.|Department of Natural Products Chemistry, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Xihuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Lianru
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Bang-Guo
authors.initials: BG
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University , Xiamen, Fujian 361102, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University , Xiamen, Fujian 361102, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D045325:HCT116 Cells; D018922:HL-60 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017382:Reactive Oxygen Species; C554215:lagunamide A
keywords: Bcl-2 family; apoptosis; lagunamide A; marine natural products; mitochondria