title: Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms.
abstract: BACKGROUND
  Aloperine, a natural alkaloid constituent isolated from the herb Sophora alopecuroides displays anti-inflammatory properties in vitro and in vivo. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. However, its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated.
  
  
  METHODS
  Human myeloma cell lines (n = 8), primary myeloma cells (n = 12), drug-resistant myeloma cell lines (n = 2), and animal models were tested for their sensitivity to aloperine in terms of proliferation and apoptosis both in vitro and in vivo, respectively. We also examined the functional mechanisms underlying the apoptotic pathways triggered by aloperine.
  
  
  RESULTS
  Aloperine induced MM cell death in a dose- and time-dependent manner, even in the presence of the proliferative cytokines interleukin-6 and insulin-like growth factor I. Mechanistic studies revealed that aloperine not only activated caspase-8 and reduced the expression of FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein long (FLIPL) and FLICE-inhibitory proteins (FLIPS) but also activated caspase-9 and decreased the expression of phosphorylated (p)-PTEN. Moreover, co-activation of the caspase-8/cellular FLICE-inhibitory protein (cFLIP)- and caspase-9/p-PTEN/p-AKT-dependent apoptotic pathways by aloperine caused irreversible inhibition of clonogenic survival. Aloperine induce more MM apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or borterzomib. A U266 xenograft tumor model and 5T33 MM cells recapitulated the antitumor efficacy of aloperine, and the animals displayed excellent tolerance of the drug and few adverse effects.
  
  
  CONCLUSIONS
  Aloperine has multifaceted antitumor effects on MM cells. Our data support the clinical development of aloperine for MM therapy.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China. Wanghe97@hotmail.com.|College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. Wanghe97@hotmail.com.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, China. 358883909@qq.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510521, China. 1452246497@QQ.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. 30552796@qq.com.
authors.forename: Mingna
authors.initials: M
authors.lastname: Sun
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. 87947067@qq.com.
authors.forename: Lingran
authors.initials: L
authors.lastname: Du
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. 53273520@qq.com.
authors.forename: Minyan
authors.initials: M
authors.lastname: Wei
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. haifengteng88@163.com.
authors.forename: Meixia
authors.initials: M
authors.lastname: Luo
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. yinghengh@126.com.
authors.forename: Jingzhu
authors.initials: J
authors.lastname: Huang
authors.affiliation: School of the Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China. denghongzhu00@126.com.
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Deng
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. drywater888@gmail.com.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: College of Basic Medicine, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. Hj164@sina.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China. Zhouyi0264@126.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology*; D054837:Quinolizidines; D034741:RNA, Small Interfering; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D054837:Quinolizidines; D034741:RNA, Small Interfering; C062701:aloperine