Trans-scirpusin A showed antitumor effects via autophagy activation and apoptosis induction of colorectal cancer cells.

Eun-Hye Hong,Young-Won Chin,Yaejeong Park,Sun-Young Chang,Sang-Min Jeon,Eun-Young Heo,Bo-Eun Kwon,Jinwoong Kim,Hyun-Jeong Ko,Jae-Hyoung Song,Jae-Young Lee

doi:10.18632/oncotarget.17388

Abstract

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.

Highlights

Polyphenols are produced as secondary metabolites in plants and are consumed as part of a normal diet by humans [1]
Trans-Scirpusin A (TSA) inhibited the growth of colorectal cancer cells
The level of TNF-α mRNA, which may be critical for the induction of apoptosis in Her2/CT26 cells in vivo, was significantly increased in tumor tissues of TSA-treated mice compared to vehicletreated mice (Figure 2B)

Summary

Introduction

Polyphenols are produced as secondary metabolites in plants and are consumed as part of a normal diet by humans [1]. Dietary polyphenols are found in fruits, tea, vegetables, and wine, and are mostly derivatives and isomers of flavonols, catechins and phenolic acid [1]. Polyphenols are documented to have multiple properties including antioxidant [2], antiinflammatory [3, 4], anti-atherosclerosis [5] and anticancer activities [6,7,8]. Resveratrol (3,4’,5-trihydroxy-trans-stilbene), found in the skin of grapes, blueberries, raspberries and mulberries [9], is known to be effective against bacterial and fungal infections [10, 11], cardiovascular diseases [12], metabolic diseases [13], and cancer [14,15,16]. In addition to the anti-neoplastic effect of resveratrol [20], resveratrol could be used along with irradiation and chemotherapy for cancer therapy [21], enabling its supplementary use with chemotherapy in cancer patients

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Conclusion