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Cancer Immunol Immunother. 2018 May;67(5):761-774. doi: 10.1007/s00262-018-2130-3. Epub 2018 Feb 16.

TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors.

Author information

1
CUNY Doctoral Program in Biochemistry, CUNY Graduate Center, New York, NY, 10016, USA.
2
Department of Chemistry, Building 6S, The City University of New York at The College of Staten Island, 2800 Victory Boulevard, Staten Island, NY, 10314, USA.
3
The Center for Developmental Neuroscience, City University of New York at The College of Staten Island, 2800 Victory Boulevard, Staten Island, NY, 10314, USA.
4
College of Arts and Science, New York University, New York, NY, 10003, USA.
5
Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
6
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
7
Department of Chemistry, Building 6S, The City University of New York at The College of Staten Island, 2800 Victory Boulevard, Staten Island, NY, 10314, USA. probal.banerjee@csi.cuny.edu.
8
The Center for Developmental Neuroscience, City University of New York at The College of Staten Island, 2800 Victory Boulevard, Staten Island, NY, 10314, USA. probal.banerjee@csi.cuny.edu.

Abstract

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1high (ARG1high), IL10high, inducible nitric oxide synthaselow (iNOSlow), IL12low M2-type tumor-associated macrophages (TAM) into ARG1low, IL10low, iNOShigh, and IL12high M1-type TAM in HPV+ tumors. The M1 TAM displayed sharply suppressed STAT3 and induced STAT1 and NF-kB(p65). STAT1 and NF-kB(p65) function synergistically to induce iNOS and IL12 transcription. Neutralizing IL12 signaling with an IL12 antibody abrogated TriCurin-induced intra-tumor entry of activated natural killer (NK) cells and Cytotoxic T lymphocytes (CTL), thereby confirming that IL12 triggers recruitment of NK cells and CTL. These activated NK cells and CTL join the M1 TAM to elicit apoptosis of the E6+ tumor cells. Corroboratively, neutralizing IL12 signaling partially reversed this TriCurin-mediated apoptosis. Thus, injected TriCurin elicits an M2→M1 switch in TAM, accompanied by IL12-dependent intra-tumor recruitment of NK cells and CTL and elimination of cancer cells.

KEYWORDS:

CTL; Curcumin; NK cells; Papillomavirus; TriCurin; Tumor-associated macrophages

PMID:
29453519
DOI:
10.1007/s00262-018-2130-3
[Indexed for MEDLINE]

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