Researchers unveil Honokiol brian tumor cell apoptosis and autophagy mechanism in mice

Glioblastoma multiforme (GBM) is a fast-growing glioma that develops from star-shaped glial cells that support the health of the nerve cells within the brain. It is also the most common and most aggressive cancer that begins within the brain and has limited treatment options. Therefore research into new and complementary treatments is needed. However to bring treatments into clinical settings detailed understanding of its mechanism of action is needed.

Honokiol has a variety of pharmacological actions, such as anti-inflammatory, neuroprotective, antioxidative, and anxiolytic activities. Studies also demonstrated that honokiol has antitumor effects by inhibiting proliferation, inducing apoptosis and cell cycle arrest, and suppressing migration and angiogenesis. Honokiol is also known to traverse the blood–brain barrier (BBB) and induce p53-mediated cell cycle arrest and apoptosis (a form of programmed cell death) of glioma cells (brain tumor cells). Another study showed that honokiol induces caspase-independent paraptosis (another form of programmed cell death) of leukemia cells via reactive oxygen species (ROS) production. This enticed the researchers in this study to analyze whether the observed apoptosis of brain tumor cells also works through a ROS mediated pathway.

In a biological context, reactive oxygen species (ROS) are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress, ROS levels can increase dramatically. This may result in significant damage to cell structures. This is known as oxidative stress. Hence increasing ROS in cancerous cells is a potential mechanism to kill them.

The researchers used an intracranial glioma (brain tumor) mouse model for the testing. The intracranial glioma-bearing mice were randomly divided into two groups and were intraperitoneally injected with honokiol or vehicle (placebo) two times per week for 2 weeks. In addition human glioma U87 MG cell lines were used for in-vitro analyses.

The experiment found dose and time dependent effects, more or less confirming earlier reported anti-cancer effects. In the human glioma cell lines treatment with 10 and 20 μM honokiol for 72 h did not induce autophagy. When the administered concentrations reached 40, 80, and 100 μM, honokiol caused significant 32.0%, 59.4%, and 68.4% of cells to undergo autophagy. In the timecourse experiment, cells were treated with 40 μM honokiol for 24, 48, and 72 h, percentages of cells undergoing autophagy had increased to 10.4%, 19.3%, and 34.4%, respectively.

The result that honokiol increased the percentage of autophagy of human glioma in dose- and time-dependent manners was further supported by observation that honokiol could increase levels of beclin-1, an upstream marker of autophagy, in similar pattern. Apoptosis and autophagy are classified as programmed cell death. However there is research that shows there is an interconnection between autophagy and apoptosis. Both may result in cell death and cooperate during this process. In this study, when the researchers inhibited autophagy (using 3-MA) this decreased apoptosis and the induction of more autophagy by rapamycin further caused apoptosis of glioma cells. This suggests that honokiol-induced autophagy contributes to apoptotic cell death.

The researchers also observed that when admistrating vitamine C the oxidative stress that was generated after treatment with honokiol was suppressed and resulted in a decrease in autophagic and apoptotic cell death of glioma cells. This result supports the notion honokiol-induced autophagy contributes to glioma cell death through ROS generation.

Building on previous research in combination with their new findings the authors concluded that the results indicated for the first time that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway. This study therefore shows that honokiol has a novel anticancer effect, which supports its potential as a clinical therapeutic agent in a treatment plan for brain tumors.

You can find the study here.

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