Curcumin and tumor immune-editing: resurrecting the immune system

Abstract

Curcumin has long been known to posses medicinal properties and recent scientific studies have shown its efficacy in treating cancer. Curcumin is now considered to be a promising anti-cancer agent and studies continue on its molecular mechanism of action. Curcumin has been shown to act in a multi-faceted manner by targeting the classical hallmarks of cancer like sustained proliferation, evasion of apoptosis, sustained angiogenesis, insensitivity to growth inhibitors, tissue invasion and metastasis etc. However, one of the emerging hallmarks of cancer is the avoidance of immune system by tumors. Growing tumors adopt several strategies to escape immune surveillance and successfully develop in the body. In this review we highlight the recent studies that show that curcumin also targets this process and helps restore the immune activity against cancer. Curcumin mediates several processes like restoration of CD4(+)/CD8(+) T cell populations, reversal of type-2 cytokine bias, reduction of Treg cell population and suppression of T cell apoptosis; all these help to resurrect tumor immune surveillance that leads to tumor regression. Thus interaction of curcumin with the immune system is also an important feature of its multi-faceted modes of action against cancer. Finally, we also point out the drawbacks of and difficulties in curcumin administration and indicate the use of nano-formulations of curcumin for better therapeutic efficacy.

Keywords: 3-Es; Curcumin; Hallmarks of cancer; Nanocurcumin; Tumor immune-editing; Tumor immunesurveillance.

Fig. 1

Curcumin targets the classical hallmarks of cancer: curcumin has been shown to target all the classical hallmarks of cancer. It reduces proliferative signals by interfering with pathways like NFκB, PI3K, MAPK etc. It also restores the levels of growth suppressors like TP53 and retinoblastoma protein (RB). Curcumin increases pro-apoptotic proteins like BAX, BIM, PUMA while decreasing anti-apoptotic proteins like BCL-2, BCL-XL, thus promoting apoptosis of cancer cells. Curcumin reduces angiogenesis by decreasing VEGF and angiopoetin and interfering with VEGFR signaling. Curcumin also restricts replicative immortality by reducing activity of human telomerase (hTERT). Finally curcumin reduces metastasis by targeting a host of invasion and cell adhesion related molecules like MMP, CXCR4, SLUG, SNAIL etc.

Fig. 2

The 3 E’s of tumor immunoediting: tumor formation occurs through accumulation of mutations induced by various stress factors like radiation, virus, chemicals and other carcinogens. During initial tumor growth, the tumor cells undergo dynamic interactions with the immune system, which is called tumor immunoediting and can be divided into 3 distinct phases. I. Elimination In this phase the balance is tilted towards the immune system. Large numbers of CD8⁺, CD4⁺ T cells along with NK-cells, macrophages and dendritic cells mount an effective response to the tumor. Soluble factors like IFNγ, perforin, granzyme lead to tumor cell apoptosis and elimination of cancer. II. Equilibrium In this phase an equilibrium exists between the tumor and immune system. The immune system tries to shift the balance towards elimination whereas the tumor cells also apply mechanisms to avoid immunesurveillance. III. Escape The continuous assault by the immune system may lead to development of tumor cells that are less immunogenic and can avoid the immune system. The tumor has several strategies to escape the immune system; these include induction of T cell apoptosis, blocking dendritic cell maturation and promoting generation of immunosuppressive Treg cells. Hence the balance shifts towards the tumor and tumor development can occur unhindered

Fig. 3

Curcumin enhances anti-tumor immunity: Curcumin can boost anti-tumor immunity through different mechanisms. These include: increased population of CD8⁺, andCD4⁺ T cells, along with increase in Th1 cytokines like IFNγ, which mediate tumor cell apoptosis. Curcumin can block Treg cell development, thereby decreasing immunosuppressive cytokines like IL10 and TGFβ. Curcumin also reduces tumor-induced T cell apoptosis. All these processes help to nullify the overall immunosppressive environment created by tumor and lead to tumor regression. Thus curcumin has the ability to shift the balance in favor of the immune system and reinstate immune system-mediated elimination of tumors

Fig. 4

Different strategies of curcumin nano formulation preparation: (1) Liposomes Lipophilic particles are incorporated into the hydrocarbon bilayer whereas hydrophilic molecules are incorporated into their aqueous interiors. (2) Polymeric micelles They contain both hydrophilic and hydrophobic functional groups and are hence called amphiphiles. They are formed when the concentration of amphiphiles exceeds critical micelle concentration. (3) Polymer nanoparticles Consist of intense matrix structure that can incorporate the pharmacologically active ingredients and has a high-drug loading capacity. (4) Nanogels A core shell polystyrene gel layer structure consisted of inner hydrophobic core that interacted with active pharmacological substances for high-drug yields and PEG analogue outer shell that trigger fast release of preloaded drug. (5) Nanoemulsion Thermodynamically stable dispersion of water and oil, stabilized with active surface film consist of surfactant and cotransfactent. (6) Solid lipid nanoparticles consist of solid lipid core matrix that stabilized by surfactants or emulsifier and solubilize lipophilic substances. (7) Inclusion complex: mixture of active drug ingredients primarily located in the hydrophobic cavity of bulky host molecules such as cyclodextrin. (8) Dendrimer Core–shell nanostructure generally synthesized in layer-by layer fashion where many pharmaceutical active compounds directly associated with stable physical interaction or chemical bonding. (9) Phytosomes: The phospholipid complex, obtained by pure phospholipids containing biological derivatives with active pure ingredients with definite physicochemical and spectroscopic properties. (10) Curcumin nanoparticles These are nanoparticles made from pure curcumin without any carrier conjugates. They are prepared by dissolving pure curcumin in ethanol and homogenization at high pressure with water containing 0.1 % citric acid [86]