Abstract

Pseudolaric acid B (PLAB) is one of the major bioactive components of Pseudolarix kaempferi. It has been reported to exhibit inhibitory effect on cell proliferation in several types of cancer cells. However, there is no report elucidating its effect on glioma cells and organ toxicity in vivo. In the present study, we found that PLAB inhibited growth of U87 glioblastoma cells in a dose-dependent manner with IC50 ~10 μM. Flow cytometry analysis showed that apoptotic cell death mediated by PLAB was accompanied with cell cycle arrest at G2/M phase. Using Western blot, we found that PLAB induced G2/M phase arrest by inhibiting tubulin polymerization in U87 cells. Apoptotic cell death was only partially inhibited by pancaspase inhibitor, z-VAD-fmk, which suggested that PLAB-induced apoptosis in U87 cells is partially caspase-independent. Further mechanistic study demonstrated that PLAB induced caspase-dependent apoptosis via upregulation of p53, increased level of proapoptotic protein Bax, decreased level of antiapoptotic protein Bcl-2, release of cytochrome c from mitochondria, activation of caspase-3 and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-independent apoptosis through apoptosis inducing factor (AIF). Furthermore, in vivo toxicity study demonstrated that PLAB did not induce significant structural and biochemical changes in mouse liver and kidneys at a dose of 25 mg/kg. Therefore, PLAB may become a potential lead compound for future development of antiglioma therapy.

Highlights

  • Primary brain tumors are the tumors that originate from various intracranial tissues

  • We investigated the inhibitory effect of Pseudolaric acid B (PLAB) on proliferation of U87 glioblastoma cells in vitro and simultaneously examined the toxic effect of this compound on liver and kidneys in animal mouse model

  • PLAB significantly arrested the cell cycle at G2/M phase in U87 glioblastoma cells in a dose-dependent manner. This result is consistent with previous studies that PLAB induced G2/M phase arrest in several types of human cancer cell lines [8,9,10, 14, 15]

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Summary

Introduction

Primary brain tumors are the tumors that originate from various intracranial tissues. More than 60% of brain tumors are gliomas [1]. Glioblastoma multiforme is the most common and lethal primary brain tumor in adults and accounts for at least 80% of malignant gliomas. It is called grade IV astrocytoma [2,3,4,5]. Over 12,000 patients die because of primary brain tumor in United States every year. Despite recent advances in surgery, radiation therapy, and chemotherapy, the median survival rate remains less than one year after diagnosis [1, 6, 7]

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