N‐AVAM‐Capsaicin Analogs: Potential applications in lung cancer therapy

Abstract

The nutritional compound capsaicin is the hot spicy pungent ingredient of chili peppers. Capsaicin is a pain-relieving agent and is found in several over-the counter pain medications. However, recent studies have shown that capsaicin has profound anti-neoplastic effects in several types of human cancers. The applications of capsaicin as a clinically useful drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. Previous studies have shown that addition of long-chain unsaturated fatty acyl groups in the “Region C” of capsaicin generated non-pungent compounds with extremely strong pain-relieving activity. These compounds are unsaturated N-acylvanillamides (N-AVAM-capsaicin analogs). We synthesized a panel of N-AVAM-capsaicin analogs with 0-4 double bonds in the side chain of capsaicin. We investigated the growth-inhibitory activity of these compounds with an MTT-based screening assay. We selected our “hit compound” Arvanil for further studies. Next, we compared the apoptotic activity of arvanil and capsaicin in a panel of human small cell lung cancer (SCLC) cells. We observed that the non-pungent capsaicin-analog arvanil displayed greater magnitude of apoptosis than capsaicin. Most interestingly, arvanil did not display apoptotic activity in normal lung epithelial cells. The pro-apoptotic activity of arvanil and capsaicin was mediated by elevation of intracellular calcium and activation of the calpain pathway. The pattern of uN-AVAM-induced intracellular calcium (and calpain-1,2 activity) correlated with the results obtained in the MTT assay. Therefore, the measurement of intracellular calcium may be used as a screening tool for capsaicin-mimetics with anti-cancer activity.