Abstract
Background Extracts from Viscum album L. (VE) are used in the complementary cancer therapy in Europe for decades. VE contain several compounds like the mistletoe lectins (MLs) 1-3 and viscotoxins and also several minor ingredients. Since mistletoe lectin 1 (ML-1) has been described as the main component of VE harboring antitumor activity, purified native or recombinant ML-1 has been recently used in clinical trials. MLs stimulate the immune system, induce cytotoxicity, are able to modify the expression of cancer-associated genes, and influence the proliferation and motility of tumor cells. Objective In this study our goal was to determine anticancer effects of the VE ISCADOR Qu, of recombinant ML-1 (Aviscumine), and of native ML-1 in the treatment of glioblastoma (GBM), the most common and highly malignant brain tumor in adults. Additionally we were interested whether these drugs, used in combination with a temozolomide-(TMZ)-based radio-chemotherapy, provide synergistic effects. Methods Cell culture assays, ex vivo murine hippocampal brain slice cultures, human GBM cryosections, and a xenograft orthotopic glioblastoma mouse model were used. Results In cells, the expression of the ML receptor CD75s, which is also expressed in GBM specimen, but not in normal brain, correlates with the drug-induced cytotoxicity. In GBM cells, the drugs induce cell death in a concentration-dependent manner and reduce cell growth by inducing cell cycle arrest in the G2/M phase. The cell cycle arrest was paralleled by modifications in the expression of cell cycle regulating genes. ML containing drugs, if combined with glioma standard therapy, provide synergistic and additive anticancer effects. Despite not reaching statistical significance, a single intratumoral application of Aviscumine prolonged the median survival of GBM mice longer than tumor irradiation. Moreover, intratumorally applied Aviscumine prolonged the survival of GBM-bearing mice if used in combination with irradiation and TMZ for further 6.5 days compared to the radio-chemotherapy. Conclusion Our results suggest that an adjuvant treatment of glioma patients with ML-containing drugs might be beneficial.
Highlights
Glioblastoma (GBM) is the most common malignant WHO grade IV brain tumour with an infaust prognosis
We show that CD75s expression on glioma cells correlates with their sensitivity to cell death induced by the treatment, bringing up CD75s as a putative biomarker that might predict the therapeutic efficacy of a MLbased therapy in GBM patients
Aviscumine and native mistletoe lectins (MLs)-1 were less toxic compared to ISCADOR Qu
Summary
Glioblastoma (GBM) is the most common malignant WHO grade IV brain tumour with an infaust prognosis. The failure of several new therapy approaches is mainly based on GBM characteristics like its diffuse, infiltrative growth into the brain parenchyma, its strong proliferation, massive immunosuppression, high angiogenic capacity, and its multi-drug-resistance, at least in recurrent glioma and glioma stem cells [2]. In this context, the development of drugs or identification of (natural) compounds that work in synergy with glioma standard therapy or even with novel therapeutic approaches is necessary to design an optimal therapeutic regimen for GBM patients. Our results suggest that an adjuvant treatment of glioma patients with MLcontaining drugs might be beneficial
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