Inhibitory effect and mechanism on antiproliferation of khellactone derivatives from herbal suitable for medical or food uses

Abstract

Angelica genus (umbelliferae) has traditionally been used as the medicine and health food considered alleviating several used in the treatment of cancer as well as non-cancerous diseases. Angelica purpuraefolia Chung is an endemic species and a folk medicine in Korea. We have previously reported that two natural khellactone isolated from the rhizomes of A. purpuraefolia has significant antiplasmodial activity against Plasmodium falciparum. In the present study, we scientifically evaluated the effect of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone from A. purpuraefolia on cell proliferation and apoptotic cell death. The anti-proliferative and apoptotic effects of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone (10-50 μg/ml) were subjected to in vitro evaluation using four breast (MDA-MB-231, MCF-7, HS578T, and T47D), three cervical (HeLa, SiHa, and C33A) cancer cell lines, and NIH 3T3 normal cells using FACS and western analyses. Our in vitro experiments showed that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone suppress the growth and proliferation of cancer cells at a relatively low concentration (<10 μg/ml) and induce apoptosis at a high concentration (>50 μg/ml). FACS analysis showed that the cell cycle arrest in the S/G2 phase was induced by the treatment with 10 μg/ml of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone in MDA-MB-231 cells. Western blot analysis also showed that concentration higher than 50 μg/ml of (+)-4'-decanoyl-cis-khellactone induced a time-dependent increase in the percentage of apoptotic cells. However, our results showed that (+)-4'-decanoyl-cis-khellactone uses both extrinsic and intrinsic pathways but (+)-3'-decanoyl-cis-khellactone uses only an intrinsic pathway for the apoptosis. More importantly, (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. Our data strongly suggest that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone act as an anti-cancer supplement particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase-dependent apoptosis at relatively low and high concentrations, respectively.