Abstract
Glioblastoma (GBM) is the most common primary brain tumor, accounting for approximately 40% of all central nervous system malignancies. Despite standard treatment consisting of surgical resection, radiotherapy and/or chemotherapy, the prognosis for GBM is poor; with a median survival of 14.6 months. The cancer stem cell or cancer-initiating cell model has provided a new paradigm for understanding development and recurrence of GBM following treatment. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plant, and along with its derivatives, has been shown to exhibit antitumor activity in several cancers. Here, we reported that a novel synthetic Berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of cancer stem-like cells (CSCs) in a time- and dose-dependent manner when the CSCs from four GBM patients (PBT003, PBT008, PBT022, and PBT030) were cultured. These CSCs grew in neurospheres and expressed CD133 and nestin as markers. Treatment with BBMD3 destroyed the neurosphere morphology, and led to the induction of apoptosis in the CSCs. Induction of apoptosis in these CSCs is dependent upon activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). MicroRNA-4284 (miR-4284) was shown to be over-expressed about 4-fold in the CSCs following BBMD3 treatment. Furthermore, transfection of synthetic anti-sense oligonucleotide against human miR-4284 partially blocked the anticancer effects of BBMD3 on the GBM derived CSCs. BBMD3 also increased phosphorylation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in an increase expression of phosphorylated c-Jun and total c-Fos; the major components of transcriptional factor AP-1. The JNK-c-Jun/AP-1 signaling pathway plays an important role in the induction of apoptosis in response to UV irradiation and some drug treatments. Targeting glioblastoma stem-like cells with BBMD3 is therefore novel, and may have promise as an effective therapeutic strategy for treating GBM patients.
Highlights
Glioblastoma (GBM) is the most common and lethal primary brain tumor
We show that a novel synthetic BBM derivative (BBMD3) induces apoptosis in cancer stem-like cells, which are cultured from GBM patients
We cultured and expanded short-term tumor neurospheres in serum-free stem cell media, that were derived from four primary GBM patients, (i.e., PBT003, PBT008, PBT022 and PBT030)
Summary
Glioblastoma (GBM) is the most common and lethal primary brain tumor. Despite current advances in multimodality therapy, which include surgery, radiotherapy and chemotherapy, prognosis remains very poor for patients, who typically have a median survival time of less than 15 months [1,2]. The majority of GBM lesions rapidly develop from a less malignant precursor lesion for which there is little or no clinical, radiological, or morphologic evidence, and it has been demonstrated that a highly tumorigenic subpopulation of cancer cells, called GBM stem cells, promotes resistance to chemo- and radio- therapy [3,4,5]. These cancer stem cells or tumor-initiating cells share some critical characteristics with normal neural stem cells, including expression of several biomarkers, and the ability for self-renewal, differentiation and proliferation. Progress slowing protocol development remains dependent upon further enhancement of our understanding of the processes driving cancer invasion, the onset of resistance to therapeutic interventions and mechanisms driving tumor recurrence in GBM patients
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