Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model

Cancer Lett. 2019 Feb 28;443:25-33. doi: 10.1016/j.canlet.2018.11.027. Epub 2018 Nov 29.

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of isolinderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.

Keywords: Brain tumor; Herb extract; Lindera aggregata; Radix Linderae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Lindera / chemistry
  • Mice
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proteomics / methods
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sesquiterpenes / administration & dosage*
  • Sesquiterpenes / pharmacology
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Sesquiterpenes
  • linderalactone
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3