Abstract
Chemo-resistance is an obstacle in therapy of lung cancer. Alternative therapy of using herbal medicine has been proposed to resolve this obstacle. Yu Ping Feng San (YPFS), a common Chinese herbal medicinal mixture, has been reported to show anti-drug resistance on cisplatin (DDP), a common lung cancer drug. To optimize the anti-cancer function of YPFS, different Chinese herbal extracts having known function to overcome lung cancer were screened in combining with YPFS, as to increase the efficacy of DDP in drug resistance lung cancer cell, A549/DDP. Amongst these herbal extracts, Ginkgo Folium exhibited the most promoting sensitized effect. This revised herbal formula, named as YPFS+GF, promoted the DDP-induced toxicity by over 2-fold as compared to that of YPFS alone; this potentiation was confirmed by inducing cell apoptosis. The anti-drug resistance of YPFS, triggered by an increase of intracellular concentration of DDP, was accompanied by an increased expression and activity of WT1, which consequently decreased the transcript level of MVP. In addition, the MVP-mediated downstream effector mTOR2/AKT was disrupted after application of YPFS+GF in DDP-treated A549/DDP cell: this disruption was characterized by the decline of mTORC2 components, e.g., Rictor, p-mTOR, as well as the phosphorylation level of its downstream protein AKT. The disruption on mTORC2/AKT could be reversed by mTORC2 inducer insulin and promoted by mTORC2 inhibitor PP242. Thus, the anti-drug resistance of YPFS+GF in DDP-treated lung cancer cells might be mediated by the down regulation of WT1/MVP axis, as well as the downstream anti-apoptotic pathway of mTORC2/AKT signaling. Herbal medicine is one of the main adjuvant therapies in non-small cell lung cancer, and this novel herbal formula supports the prescription of traditional Chinese medicine in cancer treatment.
Highlights
Non-small cell lung cancer is the major type of lung cancer accounting approximately 80% of lung cancer patients today (Haghgoo et al, 2015)
One mg/mL of Yu Ping Feng San (YPFS), a dose previously shown to achieve sub-maximal efficiency (Lou et al, 2016), was combined with the herbal extract at 0.25 mg/mL, a minimal dose routinely used in cell culture, and the mixed herbal extract was applied onto the DDP-treated cultured A549/DDP cells
The novel herbal formula composed of YPFS + Gingkgo Folium extract in a weight ratio of 4:1, named as YPFS+Ginkgo Folium (GF), showed relatively high IC50 (29.2 mg/ml) in human umbilical vein endothelial (HUVEC) cells, and slightly decrease the cytotoxicity of DDP in HUVEC cells, suggesting the non-cytotoxicity of this herbal extract in culture (Supplementary Figure 3)
Summary
Non-small cell lung cancer is the major type of lung cancer accounting approximately 80% of lung cancer patients today (Haghgoo et al, 2015). MVP is a basic component of the vault complex and forms the outer shell of vault: this is over expressed in multidrug-resistant lung cancer cells. In line to this observation, MVP is being considered to be a biomarker of drug resistance (Berger et al, 2009). Combination of DDP with other drugs is considered to be a good strategy to address drug resistance in cancer therapy; synthesized compounds usually exhibit stronger side effects. Under this scenario, the focus has been shifted to safe herbal products. Statistical analysis from clinical reports of Chinese medicine hospital during 1989 to 2007 indicated that the most frequently used medicinal herbs in lung carcinoma are those having function of replenishing “Qi” and nourishing “Yin” to lung
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