Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas

Abstract

// Yu-Chen Cheng 1 , Dueng-Yuan Hueng 2, 3 , Hua-Yin Huang 1 , Jang-Yi Chen 4 , Ying Chen 1, 4 1 Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan 2 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 3 Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan 4 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan Correspondence to: Ying Chen, e-mail: ychen0523@mail.ndmctsgh.edu.tw Keywords: honokiol, magnolol, autophagy, apoptosis, glioblastoma Received: November 30, 2015      Accepted: March 28, 2016      Published: April 11, 2016 ABSTRACT Glioblastoma (GBM) is a malignant brain tumor associated with a high mortality rate. The aim of this study is to investigate the synergistic effects of honokiol (Hono) and magnolol (Mag), extracted from Magnolia officinalis , on cytotoxicity and inhibition of human GBM tumor progression in cellular and animal models. In comparison with Hono or Mag alone, co-treatment with Hono and Mag (Hono-Mag) decreased cyclin A, D1 and cyclin-dependent kinase 2, 4, 6 significantly, leading to cell cycle arrest in U87MG and LN229 human glioma cells. In addition, phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, and Ki67 were decreased after Hono-Mag treatment, showing proliferation inhibition. Hono-Mag treatment also reduced p-p38 and p-JNK but elevated p-ERK expression. Besides, Hono-Mag treatment induced autophagy and intrinsic and extrinsic apoptosis. Both ERK and autophagy inhibitors enhanced Hono-Mag-induced apoptosis in LN229 cells, indicating a rescuer role of ERK. In human GBM orthotopic xenograft model, the Hono-Mag treatment inhibited the tumor progression and induced apoptosis more efficiently than Temozolomide, Hono, or Mag group. In conclusion, the Hono-Mag exerts a synergistic anti-tumor effect by inhibiting cell proliferation and inducing autophagy and apoptosis in human GBM cells. The Hono-Mag may be applied as an adjuvant therapy to improve the therapeutic efficacy of GBM treatment.