Abstract
During the last decade, we have persistently addressed the question, “how can the innate immune system be used as a therapeutic tool to eliminate cancer?” A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.
Highlights
Nitric oxide (NO) is produced from the amino acid arginine by the action of three types of nitric oxide synthases (NOS): neuronal NOS, inducible NOS, and endothelial NOS [1]. nNOS occurs in specific brain neurons; iNOS can be induced by cytokines in a wide variety of cells, including innate immune cells such as microglia and macrophages to fight pathogens and cancer cells; and eNOS is expressed by the endothelial tissue, cardiac myocytes, platelets, certain brain neurons, syncytiotrophoblasts of the placenta, and kidney epithelial cells [2]
(iNOS or NOS2), and endothelial NOS [1]. nNOS occurs in specific brain neurons; iNOS can be induced by cytokines in a wide variety of cells, including innate immune cells such as microglia and macrophages to fight pathogens and cancer cells; and eNOS is expressed by the endothelial tissue, cardiac myocytes, platelets, certain brain neurons, syncytiotrophoblasts of the placenta, and kidney epithelial cells [2]
This article focuses on iNOS, which is induced in stimulated macrophages that primarily kill microbes [6] but can be used with appropriate adjustments to eliminate cancer cells
Summary
Perspective on Cancer Therapy: Changing the Treaded Path? Doctoral Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA. Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA. Current address: Department of Cardiothoracic Surgery, Weill Cornell Medicine—New York Presbyterian.
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