hispidulin and Glioblastoma

Glioblastoma is an aggressive malignancy, which is notorious for its poor prognosis. Although Temozolomide (TMZ) has been showed to be an effective chemotherapeutic agent for glioblastoma treatment, the response rate is far from satisfactory. As a natural compound with anti-cancer activity against a variety of cancers, Hispidulin is a good candidate drug for combination therapy. This study is designed to determine whether Hispidulin could potentiate the anti-tumor activity of TMZ in glioblastoma. Cell proliferation and apoptosis were determined by MTT assay and Hoechst staining, respectively. Expression of proteins relevant to apoptosis and proliferation was detected by Western blotting. Our in vitro assays showed that Hispidulin enhanced the anti-tumor activity of TMZ in glioblastoma by both inhibiting cell proliferation and inducing cell apoptosis. The anti-tumor activity of Hispidulin and the enhanced TMZ anti-tumor activity by Hispidulin induced the activation of AMPK signaling pathway. Our results showed that Hispidulin, by activating AMPK, exhibited anti-tumor activity and potentiated the anti-tumor activity of TMZ in glioblastoma. Although further preclinical and clinical studies are needed, this study provides insight for using Hispidulin as a chemosensitizing agent in clinic settings.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dacarbazine; Drug Synergism; Enzyme Activation; Flavones; Glioblastoma; Humans; Reactive Oxygen Species; Signal Transduction; Temozolomide; TOR Serine-Threonine Kinases

Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. Despite recent therapeutic advances in other cancers, the treatment of GBM remains ineffective and essentially palliative. The current focus lies in the finding of components that activate the AMP-activated protein kinase (AMPK), one key enzyme thought to be activated during the caloric restriction (CR). In the present study, we found that treatment of hispidulin, a flavone isolated from Saussurea involucrate Kar. et Kir., resulted in dose-dependent inhibition of GBM cellular proliferation. Interestingly, we show that hispidulin activated AMPK in GBM cells. The activation of AMPK suppressed downstream substrates, such as the mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and resulted in a general decrease in mRNA translation. Moreover, hispidulin-activated AMPK decreases the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). Furthermore, hispidulin blocked the progression of the cell cycle at the G1 phase and induced apoptosis by inducing p53 expression and further upregulating p21 expression in GBM cells. On the basis of these results, we demonstrated that hispidulin has the potential to be a chemopreventive and therapeutic agent against human GBM.

Topics: Apoptosis; Brain Neoplasms; Cell Division; Cell Line, Tumor; Enzyme Activation; Flavones; Glioblastoma; Humans; Proto-Oncogene Proteins c-akt