Anti‐invasive and anti‐metastatic activity of capsaicin and natural capsaicin‐like compounds in lung adenocarcinoma

Lung adenocarcinoma (LAC) accounts for about 65% of all non-small cell lung cancer (NSCLC) cases. A considerable proportion of LAC patients present (in the clinic) with local and distant metastasis at the time of their diagnosis. One of the earliest events of the metastatic pathway is the invasion of malignant cells through the surrounding extracellular basement membrane into the neighboring blood vessels and lymph nodes. The long-term goal of our laboratory is to identify nutrition-based agents which will suppress the distant metastasis of human LACs. Capsaicin is the pungent ingredient of chili peppers. Published reports have revealed that capsaicin inhibits the invasion and metastasis of several types of human cancers including melanoma, prostate cancer, and cholangiosarcoma. However, the clinical application of capsaicin as an anti-cancer drug is limited by its unpleasant side-effect profile. This led us to compare the anti-metastatic activity of capsaicin with natural non-pungent capsaicin-like compounds, namely capsiate and capsiconiate. The structure and bioactivity of capsaicin closely resembles capsiate. There are no published reports involving the bioactivity of capsiconiate. We measured the anti-invasive activity of these compounds by two independent invasion assays, namely the Boyden chamber assay and spherical invasion assay. We found that capsaicin and capsiate displayed anti-invasive activity in three human LAC cell lines. In contrast, capsiconiate did not suppress the invasion of any LAC cell lines. Furthermore, we tested the anti-metastatic activity of capsaicin in a syngeneic mouse model of metastasis. We observed that the daily dietary administration of 20mg capsaicin/kg food in AIN-76A diet (with 5% lipid level) robustly decreased the area metastatic foci (in the lung) relative to vehicle-treated mice. We also investigated the signaling pathway underlying the anti-invasive activity of capsaicin. Our results show that capsaicin inhibits the invasion of human LAC cells via the TRPV6 receptor and the tyrosine phosphatase activity pathway. The data obtained from our research fosters the hope of nutrition-based therapies in metastatic lung cancer.