Sulforaphane enhances temozolomide-induced apoptosis because of down-regulation of miR-21 via Wnt/β-catenin signaling in glioblastoma

J Neurochem. 2015 Sep;134(5):811-8. doi: 10.1111/jnc.13174. Epub 2015 Jun 11.

Abstract

Temozolomide (TMZ) has been widely used in the treatment of glioblastoma (GBM), although inherent or acquired resistance restricts the application. This study was aimed to evaluate the efficacy of sulforaphane (SFN) to TMZ-induced apoptosis in GBM cells and the potential mechanism. Biochemical assays and subcutaneous tumor establishment were used to characterize the function of SFN in TMZ-induced apoptosis. Our results revealed that β-catenin and miR-21 were concordantly expressed in GBM cell lines, and SFN significantly reduced miR-21 expression through inhibiting the Wnt/β-catenin/TCF4 pathway. Furthermore, down-regulation of miR-21 enhanced the pro-apoptotic efficacy of TMZ in GBM cells. Finally, we observed that SFN strengthened TMZ-mediated apoptosis in a miR-21-dependent manner. In conclusion, SFN effectively enhances TMZ-induced apoptosis by inhibiting miR-21 via Wnt/β-catenin signaling in GBM cells. These findings support the use of SFN for potential therapeutic approach to overcome TMZ resistance in GBM treatment. Our studies indicate that sulforaphane (SFN) enhances temozolomide (TMZ)-induced apoptosis because of down-regulation of miR-21 through Wnt/β-catenin signaling in glioblastoma (GBM) cells. These findings demonstrate SFN could be considered as a potential adjuvant therapeutic agent in treating GBM patients combined with TMZ in the future to affect resistance emergence. The further explorations are essential for the clinical application of SFN in GBM patients, and our results reveal an important mechanism of SFN chemopreventive and chemotherapeutic activity. Chr17, chromosome 17.

Keywords: Wnt/β-catenin signaling; apoptosis; glioblastoma; miR-21; sulforaphane; temozolomide.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Down-Regulation / drug effects
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Isothiocyanates / pharmacology
  • Isothiocyanates / therapeutic use*
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • MicroRNAs / physiology
  • Models, Biological
  • Neoplasm Proteins / physiology
  • Phytotherapy
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / physiology
  • Random Allocation
  • Temozolomide
  • Wnt Signaling Pathway / physiology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • Antineoplastic Agents, Phytogenic
  • Isothiocyanates
  • MIRN21 microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Neoplasm
  • Dacarbazine
  • sulforaphane
  • Temozolomide