Anti-cancer Effects of Polyphenolic Compounds in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer

Abstract

Background: Polyphenolic phytochemicals are natural compounds, easily found in fruits and vegetables. Importantly, polyphenols have been intensively studied as excellent antioxidant activity which contributes to anticancer function of the natural compounds. Lung cancer has been reported to mainly account for cancer-related deaths in the world. Moreover, epidermal growth factor receptor tyrosine kinase inhibitor (TKI) resistance is one of the biggest issues in cancer treatment, especially in nonsmall cell lung cancer (NSCLC). Even though several studies both in preclinical and clinical trials have showed promising therapeutic effects of polyphenolic compounds in anticancer therapy, the function of the natural compounds in TKI-resistant (TKIR) lung cancer remains poorly studied.

Objective: The aim of this study is to screen polyphenolic compounds as potential anticancer adjuvants which suppress TKIR lung cancer.

Materials and methods: Colony formation and thiazolyl blue tetrazolium blue assay were performed in the pair-matched TKI-sensitive (TKIS) versus TKIR tumor cell lines to investigate the therapeutic effect of polyphenolic compounds in TKIR NSCLC.

Results: Our data show that equol, kaempferol, resveratrol, and ellagic acid exhibit strong anticancer effect in HCC827 panel. Moreover, the inhibitory effect of most of tested polyphenolic compounds was highly selective for TKIR lung cancer cell line H1993 while sparing the TKIS one H2073.

Conclusion: This study provides an important screening of potential polyphenolic compounds for drug development to overcome TKI resistance in advanced lung cancer.

Summary: The study provides an important screening of potential polyphenolic compounds for drug development to overcome tyrosine kinase inhibitor (TKI) resistance in advance lung cancerEquol, kaempferol, resveratrol, and ellagic acid show strong anticancer effect in HCC827 panel, including TKI-sensitive (TKIS) and TKI-resistant clonesThe inhibitory effect of polyphenolic compounds such as equol, kaempferol, resveratrol, ellagic acid, gallic acid, p-Coumaric, and hesperidin is highly selective for TKI-resistant lung cancer cell line H1993 while sparing the TKIS one H2073. Abbreviations used: EGFR: Epidermal growth factor receptor, EMT: Epithelial-to-mesenchymal transition, GTP: Green tea polyphenols, IGF1R: Insulin-like growth factor 1 receptor, MET: Met proto-oncogene, MTT: Thiazolyl blue tetrazolium blue, NSCLC: Non-small cell lung cancer, ROS: Reactive oxygen species, RTK: Receptor tyrosine kinase, STAT3: Signal transducer and activator of transcription 3, TKIR: TKI-resistant, TKIs: Tyrosine kinase inhibitors, TKIS: TKI-sensitive.

Keywords: Epidermal growth factor receptor tyrosine kinase inhibitor resistance; lung cancer; polyphenolic compounds.

Figure 1

Selective therapeutic effect of polyphenolic phytochemicals on tyrosine kinase inhibitor resistant lung cancer cells H1993 thiazolyl blue tetrazolium blue assay was used to evaluate therapeutic effects of polyphenols in the panel of tyrosine kinase inhibitor-sensitive cells, H2073 and tyrosine kinase inhibitor-resistant cells, H1993. Lung cancer cells were treated with equol (a), kaempferol (b), resveratrol (c), ellagic acid (d), gallic acid (e), p-Coumaric acid (f), and hesperidin (g) at indicated concentration for 5 days. In every thiazolyl blue tetrazolium blue assay, values are mean ± standard error of the mean of five replicate assays. Polyphenolic compounds suppressed cancer growth of tyrosine kinase inhibitor-resistant cells H1993 while sparing tyrosine kinase inhibitor-sensitive cells H2073

Figure 2

Chemical structure of polyphenolic compounds (a-c). Polyphenolic compounds were structurally classified into three categories as follows: phenolic acid (a), shikimic acid, p-Coumaric acid, ellagic acid, gallic acid, caffeic acid, and chlorogenic acid; flavonoid (b), (+)-catechin hydrate, equol, kaempferol, quercetin dihydrate, and hesperidin; and stilbene (c), resveratrol

Figure 3

Therapeutic effect of polyphenols in the panel of HCC827 cells (a-c). Therapeutic effects of polyphenols were evaluated using colony formation assay in HCC827 clones, including tyrosine kinase inhibitor-resistant cells, HCC827C2 (a) and HCC827C1 (c); and tyrosine kinase inhibitor-sensitive cells, parental HCC827 (b). Lung cancer cells were treated with polyphenolic compounds at indicated concentration for 7 days