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Title: Structure-activity relationships of a-, ß1-, and d-Tomatines and Tomatidine Against Human Breast (MDA-MB-231), Gastric (KATO-III), and Prostate (PC3) Cancer Cells

Author
item CHOI, SUK HYUN - Seowon University, Korea
item AHN, JUN-BAE - Seowon University, Korea
item KOZUKUE, NOBUYUKI - Seowon University, Korea
item KIM, HYUN-JEONG - Keimyung University
item NISHITANI, YOSUKE - Kobe University
item MIZUNO, MASASHI - Kobe University
item Levin, Carol
item Friedman, Mendel

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2012
Publication Date: 4/18/2012
Citation: Choi, S., Ahn, J., Kozukue, N., Kim, H., Nishitani, Y., Mizuno, M., Levin, C.E., Friedman, M. 2012. Structure-activity relationships of a-, ß1-, and d-Tomatines and Tomatidine Against Human Breast (MDA-MB-231), Gastric (KATO-III), and Prostate (PC3) Cancer Cells. Journal of Agricultural and Food Chemistry. doi.org/10.1021/jf3003027.

Interpretive Summary: Tomatoes, a major food source, synthesize secondary metabolites, including the glycoalkaloids a-tomatine and dehydrotomatine, which serve as natural defenses against phytopathogenic fungi, viruses, bacteria, insects, and worms as well as against foodborne bacteria and viruses. The a-tomatine molecule consists of a steroidal part with a side chain consisting of four carbohydrates (one galactose, two glucose, and one xylose). To help define the possible roles of these sugar moieties in the inhibition of cancer cell growth, the main objective of the present collaborative study with colleagues from Korean and Japanese universities, one of whom was a visiting scientist at WRRC, is to compare the growth-inhibiting effect of a-tomatine and four hydrolysis products with side chains of three, two, one, and zero sugars against three cancer cell lines using the MTT cell viability assay. Systematic removal of one, two, or three sugar residues from a-tomatine results in the formation of compounds (metabolites) with significantly reduced inhibitory activity. Of particular interest is the observed tenfold higher activity of a-tomatine against prostate than against breast and stomach cancer cells. This observation suggests that a-tomatine merits further study to determine whether it has the potential to protect against and/or treat prostate, breast, and colon cancers in humans.

Technical Abstract: Partial acid hydrolysis of the tetrasaccharide (lycotetraose) side chain of the tomato glycoalkaloid a-tomatine resulted in the formation of four products with three (ß1-tomatine), two ('-tomatine), one (d-tomatine), and zero (tomatidine) sugar residues. These compounds were isolated by chromatography on an aluminum oxide column and their structures were then determined by thin-layer chromatography (TLC) and LCMS-IT-TOF mass spectrometry. We then determined the inhibition by the five compounds of normal human liver and lung cells, and human breast, gastric and prostate cancer cells. The results indicate that the removal of sugars significantly reduced the concentration-dependent cell-inhibiting effects of the test compounds. IC50 values (dose-dependent concentration that inhibited 50% of the cells) showed that the PC3 prostate cancer cells were about 10 times more susceptible to inhibition by a-tomatine than was the breast and gastric cancer cells or the normal cells. The IC50 value of a-tomatine of against the prostate cancer cells was 200 times lower (the activity was higher) than that of the aglycone tomatidine. IC50 values decreased (activity increased) as the number of sugars on the aglycone increased, but this was only statistically significant at p<0.05 for the Hel299 cell line. In a separate assay, the effect of the alkaloids on tumor necrosis factor a (TNF-a) was measured in RAW264.7 macrophage cells. TNF-a was reduced at the highest dosage of tomatidine, and d-, ', and a-tomatine, but not by ß1-tomatine. There was a statistically significant negative correlation between dosage of '- and a-tomatine and the level of TNF-a. a-Tomatine was the most effective compound at reducing TNF-a. The possible mechanisms of the anti-cancer effects and the dietary significance of the results are discussed.