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

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.

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

“…For example, in the genetic IL‐10 –/– model of colitis, we showed that resveratrol treatment was able to induce immunosuppressive MDSCs that led to a reduction in clinical parameters in addition to the reduction in CXCR3 expressing T cells . The ability of resveratrol to induce these anti‐inflammatory MDSCs has been shown in our laboratory in other disease models, and been confirmed by others as well . Other studies have shown that the beneficial effects of resveratrol against colitis can be attributed to other mechanisms, such as targeting sphingosine kinase 1 (SphK1) and apoptosis, restoring nitric oxide levels, reducing neutrophil infiltration, inhibiting NF‐κB activation, acting as an antioxidant, as well as inhibiting adhesion molecules .…”

“…13 The ability of resveratrol to induce these anti-inflammatory MDSCs has been shown in our laboratory in other disease models, [8][9][10] and been confirmed by others as well. 31,32 Other studies have shown that the beneficial effects of resveratrol against colitis can be attributed to other mechanisms, such as targeting sphingosine kinase 1 (SphK1) and apoptosis, restoring nitric oxide levels, reducing neutrophil infiltration, inhibiting NF-B activation, acting as an antioxidant, as well as inhibiting adhesion molecules. [33][34][35] Resveratrol is also well known to be a ligand for the aryl hydrocarbon receptor (AhR), and our laboratory and others have shown this natural compound's ability to shift T cell differentiation from Th17 to Tregs, which is dependent on this receptor-ligand interaction.…”

Polyphenols: Immunomodulatory and Therapeutic Implication in Colorectal Cancer

“…Trans -Scirpusin A (TSA), a resveratrol oligomer, has been reported to inhibit the growth of colorectal cancer in in vivo model. Among different mechanisms involved in its antitumor efficacy, TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25-FoxP3 regulatory T cells and myeloid-derived suppressor cells (73).…”

ERdj5 in Innate Immune Cells Is a Crucial Factor for the Mucosal Adjuvanticity of Cholera Toxin

“…SDS-PAGE and western blotting was conducted as previously described (25). Briefly, cell lysates were evaluated to determine protein levels and then loaded on SDS-PAGE gel.…”