Abstract
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 O 6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O 6-benzylguanine (O 6-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.
Highlights
Malignant brain tumor is one of the most lethal cancers in adults
We investigated the effects of Honokiol on the elimination of cancer stem cells (CSCs) and the reversal of TMZ resistance in GBM8401 side population (SP) cells, and studied what underlying mechanisms are responsible
Human glioblastoma multiforme GBM8401 cells were maintained with Dulbecco's Modified Eagle Medium (DMEM) and human glioblastoma/anaplastic astrocytoma U87 MG cells were maintained in Eagle's Minimum Essential Medium (MEM)
Summary
Malignant brain tumor is one of the most lethal cancers in adults. Grade III and IV are malignant gliomas that are lethal within few years and 9–12 months, respectively [2]. High-grade glioma (glioblastoma multiforme, GBM), the most frequent and malignant brain tumor in adults are typically resistant to radiotherapy and chemotherapy. The survival of GBM after surgery and radiotherapy was limited in one year. The chemotherapy, such as Temozolomide (TMZ), could further prolong the survival up to about twenty months [3], but most patients died within two years. Searching for innovative therapeutic agents and developing novel strategies for refractory GBM patients are imperative and urgent
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