The anti-proliferative and anti-metastatic effects of the ethanol extract of Coriolus versicolor

Abstract

Lung cancer is a major issue in our current society. In 2012, the number of global lung cancer patients was estimated at 8.2 million, with an expected incidence rate of 1.8 million new cases. Of all the cancer types, lung cancer is also the most lethal, with a 19.4% mortality rate. Of all lung cancers, non-small cell lung cancer (NSCLC) is the most prevalent diagnosis. Although there are approved therapies for lung cancer, the majority of them focus on growth proliferation inhibition, or inducing apoptosis to reduce the tumor load of a patient. One aspect of NSCLC diagnosis is that patients are usually in the latter stages of cancer, indicating that the tumor is on the cusp of metastasizing, or has already done so. To date, there are no drugs available for a patient capable of inhibiting metastasis. There has been an increase in the use of herbal medicine in the past few decades. The prevalent view is to enhance general health, along with the desire to increase the effects of cancer drug treatment. Traditional Chinese Medicine (TCM) has also been proven to be a ‘treasure trove’ of novel therapeutic compounds, due to its long history of clinical use. In this project, the ethanol extract of the fruiting body of Coriolus versicolor (ECV), a bracket fungus commonly known as Turkey tail, was studied. In the first part of the study, ECV and its fractions were tested for anti-proliferative effects on the A549 non-small cell lung carcinoma cell line. The sixth fraction (S6) was found to be responsible for these effects. Further screening determined that ECV and S6 were capable of inhibiting TGFβ induced A549 metastasis via the suppression of MMP2 gelatinase activity. In the second part of the study, further focus was placed upon the underlying mechanisms of inhibition against TGFβ induced epithelial-mesenchymal transition (EMT). ECV and S6 abrogated the TGFβ induced phosphorylation of Smad 2/3 and Akt. Further details demonstrated that S6 was capable of suppressing Slug mRNA transcription. Strikingly, rather than restore E-cadherin expression at the protein or mRNA level, ECV and S6 pre-treatments enhanced the suppressive effects of TGFβ on E-cadherin. In contrast to these effects, ECV and S6 also suppressed TGFβ induced vimentin expression. The third part of the study focused on the anti-proliferative aspect. The treatment of A549 NSCLC with S6 demonstrated a dose-dependent suppression of A549 NSCLC and HK2 proximal renal tubule cell viability. In the A549 cell line, high doses of S6 were found to significantly induce apoptosis, whilst treatment of HK2 cells with S6 induced necrosis. Cell cycle analysis with ECV and S6 in the A549 cell line indicated that the anti-proliferative effects were due to dysregulation of the cell cycle at the G1/S and G2/M checkpoints. These effects were mediated through the suppression of CDK 2, 4, and 6 protein expression. ECV and S6 treatment also led to the induction of p53 and p21 expression. Taken together, these results indicate that S6 is a potential candidate for continued drug development for late stage NSCLC treatment, either to suppress the growth of cancer cells or to reduce metastasis.