Ixocarpalactone A isolated from the Mexican tomatillo shows potent antiproliferative and apoptotic activity in colon cancer cells

• Published in: The FEBS journal 2006-12, Vol.273 (24), p.5714-5723
• Main Authors: Choi, Juliana K., Murillo, Genoveva, Su, Bao‐Ning, Pezzuto, John M., Kinghorn, A. D., Mehta, Rajendra G.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry; Cell Cycle - drug effects; Cell Line, Tumor; Chemotherapy; colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colorectal cancer; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; E2F1 Transcription Factor - metabolism; Ergosterol - analogs & derivatives; Ergosterol - chemistry; Ergosterol - therapeutic use; Humans; ixocarpalactone A; Mexico; Pharmacology; Physalis - chemistry; Physalis philadelphica; Phytotherapy; Proteins; Retinoblastoma Protein - metabolism; tomatillo; Transcription Factor DP1 - metabolism; Up-Regulation - drug effects; Vegetables
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2006.05560.x

Physalis philadelphica Lam, commonly known as a tomatillo, is a staple of the Mesoamerican cuisine. In our laboratory, an ethyl acetate‐soluble extract and four withanolides [ixocarpalactone A (IxoA), ixocarpalactone B, philadelphicalactone B, and withaphysacarpin] were isolated. Studies conducted on Hepa‐1c1c7 hepatoma cells revealed that withanolides were potent inducers of quinone reductase, suggesting possible cancer chemoprotective activity. Here we evaluated the antiproliferative properties of the withanolides in SW480 human colon cancer cells. IxoA, which is present in the edible part of the tomatillo, was selected for further evaluation. SW480 cells treated with IxoA showed cell cycle arrest in the G2/M phase, up‐regulation of hyper‐phosphorylated retinoblastoma, and down‐regulation of E2F‐1 and DP‐1. On the basis of flow cytometry analysis, ethidium bromide/acridine orange, and 4′,6‐diamidino‐2‐phenylindole staining, it was found that IxoA induces apoptosis in SW480 cells. Moreover, increased concentrations of the pro‐apoptotic protein, BIM/BOD, were found by western blot analysis and immunocytochemistry. Morphological examination revealed vacuole formation in cells treated with IxoA, and Oil Red O staining showed that the vacuole content was nonlipid. Furthermore, immunocytochemistry demonstrated increased concentrations of mucin 3 in IxoA‐treated SW480 cells. These findings suggest that chemicals present in tomatillos (e.g. IxoA) may have cancer chemopreventive properties.