br Contents lists available at ScienceDirect br Journal
Contents lists available at ScienceDirect
Journal of Functional Foods
journal homepage: www.elsevier.com/locate/jff
Anti-pancreatic-cancer eﬀect of a newly bred cabbage line, Amtak- T
ssamchae, is mediated by a reduction in regulatory-T-cell recruitment
Sunggun Kima,1, Soo Jeong Kimb,1, Eun-Sang Joa, Kicheol Gilb, Na-Yeon Kima, Ji Sung Parkc, Dongbok Parkc, So-Young Parka, , Kwang Woo Hwangb,
a College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 31116, Republic of Korea
b College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
Regulatory T cell β-carotene Chemokine receptor
Chemokine receptor ligand
We aimed to investigate possible anticancer eﬀects of Amtak-ssamchae (a newly bred cabbage line containing more carotenoids) in an in vitro pancreatic-tumor cell model and an in vivo model (Panc02 cells). In an in vitro assay, Amtak-ssamchae significantly reduced the viability of Panc02 cells relative to normal ssamchae. Furthermore, an Amtak-ssamchae extract significantly reduced the tumor size in mice inoculated with Panc02 cells, and this eﬀect was accompanied by changes in the cell population in/near the tumor and spleen. Treatment with the extract of the new cabbage line blocked regulatory-T-cell recruitment, which is known as the main pathological mechanism of action of pancreatic cancer to avoid host immunity. Additionally, Amtak-ssamchae (not the normal line) contained β-carotene (at 27.9 ± 2.1 μg/g). Thus, we suggest that the Amtak-ssamchae extract could be a resource for natural supplements and functional foods for combating pancreatic cancer.
Pancreatic cancer (PC) is defined as a malignant pancreatic tumor and has a high mortality rate because it can hardly be diagnosed before reaching an advanced stage (Oberstein & Olive, 2013; Siegel, Miller, & Jemal, 2015). It has been reported that suppression of the immune system in the host is important for the survival of PC cells (Bazhin, Bayry, Umansky, Werner, & Karakhanova, 2013; Morse, Hall, & Plate, 2009). The microenvironment of a pancreatic tumor is thought to be aﬀected by regulatory T cells (Tregs), which are a subpopulation of CD4+ T cells that express IL-2Rα-chain (CD25) and forkhead box P (FOXP3) and play an important role in the maintenance of immune tolerance to self and foreign Z-Guggulsterone at peripheral sites by inhibiting T-cell responses (Fontenot, Gavin, & Rudensky, 2003; Shevach, 2011). The importance of Tregs in PC has been demonstrated not only in a mouse model of PC but also in human PC patients (Ghansah et al., 2013;
Hiraoka, Onozato, Kosuge, & Hirohashi, 2006; Yamamoto et al., 2012). Thus, describing the parameters of Tregs in PC as well as immune-system–associated organs such as the spleen is crucial for understanding the pathogenesis of PC.
The number of Tregs is elevated among/near pancreatic tumor cells because Tregs are attracted and captured abnormally by a parncreatic tumor (Singh et al., 2018). Chemokine receptor (CCR) expressed on Tregs is known to interact with the chemokine receptor ligand (CCL) on the surface of pancreatic tumor cells. This chemotaxis allows Tregs to migrate to the pancreatic tumor more easily than eﬀector T cells can; thus, the immune system nearby is successfully compromised. Besides, this alteration causes T-cell population changes in immune-system–-related organs like the spleen and lymph nodes. FOXP3, one of bio-molecules located on the surface of Treg cells is also expressed in many tumors and directly boosts tumor growth (Heinze et al., 2009; Karanikas et al., 2008). It is known that FOXP3+ PC can suppress the
Abbreviations: APC, allophycocyanin; CCL, chemokine receptor ligand; CCR, chemokine receptor; ELISA, enzyme-linked immunosorbent assay; FITC, fluorescein isothiocyanate; HBSS, Hank’s balanced salt solution; HPLC, high-performance liquid chromatography; IACUC, institutional animal care and use committee; IC50, half-maximal inhibitory concentration; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NK, natural killer; Normal Leaves: NL, normal ssamchae; PBS-T, 0.05% Tween 20 in PBS; PC, pancreatic cancer; PE, phycoerythrin; anti-Tumor Leaves: TL, Amtak-ssamchae; Tregs, regulatory T cells
Corresponding authors at: Laboratory of Pharmacognosy, College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 31116, Republic of Korea (S.-Y. Park). Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea (K.W. Hwang). E-mail addresses: [email protected] (S.-Y. Park), [email protected] (K.W. Hwang).
1 These authors equally contributed to this work.
Fig. 1. Outline of the in vivo study from the injection of pancreatic cancer cells to euthanasia. When this experiment ended, all animals were taken down to collect tumor tissue and spleens (NL: NL treated group with a tumor inoculation, TL: TL treated group with a tumor inoculation).