Abstract
The steroidal alkaloid tomatidine is an aglycone of α-tomatine, which is abundant in tomato leaves and has several biological activities. Tomatidine has been reported to inhibit the growth of cultured cancer cells in vitro, but its anti-cancer activity in vivo and inhibitory effect against gastric cancer cells remain unknown. We investigated the efficacy of tomatidine using human gastric cancer-derived 85As2 cells and its tumor-bearing mouse model and evaluated the effect of tomatidine-rich tomato leaf extract (TRTLE) obtained from tomato leaves. In the tumor-bearing mouse model, tumor growth was significantly inhibited by feeding a diet containing tomatidine and TRTLE for 3 weeks. Tomatidine and TRTLE also inhibited the proliferation of cultured 85As2 cells. Microarray data of gene expression analysis in mouse tumors revealed that the expression levels of mRNAs belonging to the type I interferon signaling pathway were altered in the mice fed the diet containing tomatidine and TRTLE. Moreover, the knockdown of one of the type I interferon-stimulated genes (ISGs), interferon α-inducible protein 27 (IFI27), inhibited the proliferation of cultured 85As2 cells. This study demonstrates that tomatidine and TRTLE inhibit the tumor growth in vivo and the proliferation of human gastric cancer-derived 85As2 cells in vitro, which could be due to the downregulation of ISG expression.
Highlights
Gastric cancer had the fourth highest incidence rate and the third highest mortality rate among cancers worldwide in 2020 [1]
Leaves are unused resources that are discarded during tomato harvesting. αTomatine has various bioactivities, such as anti-cancer, anti-viral [9], and anti-inflammatory activities [10]. α-Tomatine reduces the growth of several cultured cancer cell lines, such as LNCaP, VCaP, and PC-3, K562, and HL60 cells [11,12]
Peaks corresponding to dehydrotomatine and α-tomatine were not detected in the high-performance liquid chromatography (HPLC) chromatogram of tomatidine-rich tomato leaf extract (TRTLE) (Figure 1b), suggesting that these tomatines are almost completely aglyconated by acid hydrolysis
Summary
Gastric cancer had the fourth highest incidence rate and the third highest mortality rate among cancers worldwide in 2020 [1]. A steroidal glycoalkaloid α-tomatine is abundant in the flowers, leaves, calyxes, and unripe fruits of tomatoes (1.10, 0.98, 0.80, and 0.47 g/kg of fresh weight, respectively) [8]. The anti-cancer activity of α-tomatine has been shown in vivo, such as in the suppression of tumor formation in tumor-bearing mice using CT-26 (mouse colon cancer) cells via the intraperitoneal administration of α-tomatine (5 mg/kg body weight) [13]. Incubation with 100 μM tomatidine for 48 h inhibited the growth of HT-29 (colon adenocarcinoma), HeLa (cervical carcinoma), and MCF-7 (breast adenocarcinoma) cells in vitro by 70, 60, and 80%, respectively [16]. Incubation with 30 μM tomatidine for 24 h inhibited the growth of HBL-100 (breast cancer) cells by approximately 75% [17]. Whether tomatidine inhibits tumor growth in vivo, similar to α-tomatine, has not yet been reported. The effect of tomatidine on gastric cancer cells is unclear, as tomatidine inhibits the growth of the gastric cancer cell line KATO-III [18] but has no effect on another cancer cell line, AGS [19]
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