Journal Article

Elimination of Cancer Stem-Like Cells and Potentiation of Temozolomide Sensitivity by Honokiol in Glioblastoma Multiforme Cells

Yeh, Chi-Tai, Lui, Tai-Ngar, Shih, Ping-Hsiao, Wang-Peng, Jacqueline, Hu, Tsai-Shu, Yao, Chih-Jung, Lai, Gi-Ming, Lai, I-Chun, Chuang, Suang-En, Lai, Tung-Yuan

2015

Overview

Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antineoplastic Agents - pharmacology / Apoptosis / Basic Helix-Loop-Helix Transcription Factors - genetics / Biphenyl Compounds - pharmacology / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - pathology / Brain tumors / Cancer / Cell proliferation / Cell Proliferation - drug effects / Cell self-renewal / Chemotherapy / Dacarbazine - analogs & derivatives / Dacarbazine - pharmacology / Deoxyribonucleic acid / DNA / DNA methyltransferase / Dose-Response Relationship, Drug / Down-Regulation / Drug Synergism / Drug Therapy, Combination / Gene expression / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - genetics / Glioblastoma - pathology / Glioblastoma multiforme / Glioblastomas / Glioma / Hedgehog protein / Homeodomain Proteins - genetics / Humans / Intermediate filament proteins / Lignans - pharmacology / Methylguanine / Neoplastic Stem Cells - drug effects / Nestin / O6-methylguanine-DNA methyltransferase / Oct-4 protein / Potentiation / Prognosis / Radiation therapy / Receptor, Notch3 / Receptors, Notch - genetics / Repopulation / Stem cells / Temozolomide / Transcription Factor HES-1 / Tumor Cells, Cultured