Hispidulin Potently Inhibits Human Glioblastoma Multiforme Cells through Activation of AMP-Activated Protein Kinase (AMPK)

Abstract

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.

AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

“…AMPK is also activated by numerous drugs and xenobiotics. Some of these are in clinical use for the treatment of type 2 diabetes (e.g., metformin [Zhou et al 2001] and thiazolidinediones ), some are ''nutraceuticals'' (e.g., resveratrol from red wine [Baur et al 2006] and epigallocatechin gallate from green tea [Hwang et al 2007]), and some are plant products used in traditional herbal medicines in Europe (e.g., galegine, from which metformin was originally derived) (Mooney et al 2008) or Asia (e.g., berberine [Lee et al 2006] and hispidulin [Lin et al 2010]). One puzzling feature was how so many xenobiotics of very varied structure could all activate AMPK; it seemed unlikely that they would all bind directly to the kinase complex.…”

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

“…AMPK is also activated by many drugs and xenobiotics, including drugs used clinically in the treatment of type 2 diabetes, such as metformin (Zhou et al 2001) and thiazolidinediones . Other xenobiotics that activate AMPK include plant products that are "nutraceuticals" (e.g., resveratrol present in grapes and red wine [Baur et al 2006] and epigallocatechin gallate present in green tea [Hwang et al 2007]), and plant products used in traditional Chinese medicine (e.g., berberine [Lee et al 2006] and hispidulin [Lin et al 2010]). Interestingly, metformin was derived from galegine, a natural product of the plant Galega officinalis, which was used in traditional European herbal medicine; galegine is also a potent activator of AMPK (Mooney et al 2008).…”

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

“…Aside from this, some xenobiotic compounds, which are components of traditional herbal medicines, are also reported to have the ability in activating AMPK. These plant products include salicylate conventionally purified from willow bark [155,156], berberine extracted from Chinese Goldthread [157], resveratrol found in grapes and red wine [112,133], epigallocatechin-3-gallate found in green tea [158,159], hispidulin taken from Snow Lotus [160], the aflavins obtained from black tea [161], genistein derived from soybean [159], capsaicin that exists in Chili peppers [159], caffeic acid phenethyl ester present in honeybee propolis [162], curcumin present in turmeric Curcuma longa [114], garlic oil present in Allium sativum [163], extracts of Korean red ginseng (RGE) [113], and last but not least the extracts from bitter melon (BME) [164]. Although in most cases the mechanism of action of these natural substances in activating AMPK is still not completely understood, pilot studies have already been started in recent times to examine the effects of these dietary compounds and their potential application as a cotherapy together with standard therapeutics in malignancies especially ovarian cancer.…”