Abstract
SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.
Highlights
Glioblastoma multiforme (GBM) is the most frequent and most malignant brain tumor, with a mean survival of GBM patients of less than 2 years [1]
Since SB365 inhibited autophagic flux in GBM cells, we evaluated its influence on the anticancer
SB365 exerted a cytotoxic effect on these cells in a dose-dependent manner
Summary
Glioblastoma multiforme (GBM) is the most frequent and most malignant brain tumor, with a mean survival of GBM patients of less than 2 years [1]. Temozolomide (TMZ) is the drug of choice [4]. TMZ is an oral alkylating agent that induces DNA methylation at the O6 position of guanine. The resultant O6 -methylguanine is abnormally paired with thymine, leading to cleavage of DNA strands by the mismatch-repair system, which triggers apoptosis [5]. TMZ is suitable for treating GBM because it can pass the blood–brain barrier [6]. Resistance to TMZ can be induced in GBM cells by expression of p53, p21, or O6 -methylguanine-DNA methyltransferase (MGMT) [7]. TMZ has side effects such as genotoxicity, fetal toxicity, and lymphocytopenia of T cells and NK cells [8]
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