Honokiol shows potential as anti-metastasis drug in lung cancer

Honokiol is one of two main biphenolic compounds that are isolated from the bark, seed cones and leaves of Magnolia trees. It is widely researched and among other uses has build up a reputation as potential anti-cancer compound or enhancer of therapies. It turns off cell division in some cancer cells, and in others it induces them to kill themselves (a process called apoptosis). Honokiol also is known to promote antiangiogenisis – that means that it stops the formation of new blood vessels that feed a tumor, resulting in starvation of the tumor.

In a study published in Nature magazine beginning of September researchers examined its effects on metastasis in lung cancer. In the past it has been reported that honokiol inhibits epithelial-to-mesenchymal transition (EMT) in breast cancer, gastrointestinal cancer, renal cancer, glioblastoma cells and oral cancer but no study has examined the inhibition of EMT by honokiol in lung cancer. They were motivated by the fact that cancer metastasis is a major cause of treatment failure and death in lung cancer patients, and there is no effective method to directly target metastasis except with traditional chemotherapy.

The metastasis mechanism is poorly understood but recently it was reported that EMT, which that takes place in epithelial carcinomas (including lung cancer), has an important role in enhancing cancer motility (= ability of a cell to move) and migration. The researchers noted that EMT leads to the reduction of cell-cell adhesion. It is also known that transforming growth factor-β (TGF-β) is a major inducer of EMT in cancer cells during tumor progression and that Tumor necrosis factor-α (TNF-α) is able to accelerate the EMT process induced by TGF-β. Therefore in the study the researchers viewed and used TGF-β and TNF-α as co-stimulators of the EMT process.

In the experiment the researchers used TNF-α in combination with TGF-β1 to stimulate EMT of human non-small cell lung cancer cells (NSCLC). Cell proliferation was analyzed as well as cell motility. In addition the expression levels of relevant proteins were detected. The analyses was expanded by the use of siRNAs to knock down the gene expression of c-FLIP and N-cadherin (a mesenchymal marker) which are believed to play a key role. Similarly genes were over-expressed.

The researchers observed that treatment with TNF-α+TGF-β1 significantly enhanced the migration of NSCLC cells, increased c-FLIP, N-cadherin, snail (a transcriptional modulator) and p-Smad2/3 expression, and decreased IκB levels in the cells. Co-treatment with honokiol prevented this. Further studies demonstrated that expression level of c-FLIP was highly correlated with the movement and migration of the NSCLC cells. It was also show that the downstream effectors of c-FLIP signaling were NF-κB signaling and N-cadherin/snail signaling, while Smad signaling might lie upstream of c-FLIP.  Altogether the researchers revealed a mechanism where honokiol inhibits EMT-mediated motility and migration of human NSCLC cells in vitro by targeting c-FLIP.

The findings show that on one side c-FLIP appears to be a promising target for cancer therapy and that honokiol, besides its other anti-cancer properties, also has potential as anti-metastasis drug or lead compound for lung cancer.

It should be noted however that the study was performed in-vitro, therefore no dosing information is available and there is no efficacy data on in-vivo use. The research report can be found here.

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