Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells

Abstract

Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12–15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM): 32:8:100 (termed 32 μM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

Apigenin from Croton betulaster Müll restores the immune profile of microglia against glioma cells

“…Moreover, we also observed that the treatment of C6 cells with apigenin induced the activation and chemotaxis of microglial cells towards the glioma, restoring the microglia antitumor immune response to M1. In a similar study, Mukherjee et al () used flavonoids to treated mice with glioblastoma cells and repolarized M2‐ like tumor associated with microglia cells to the tumoricidal M1 phenotype and intra glioblastoma recruitment of natural killer cells. Quantitative analysis of chemotaxis assays showed a significant and dose‐dependent increase in microglial migration towards C6 cultures treated with apigenin compared with the controls, indicating the property of apigenin to recruit microglia cells with M1 profile to the tumor area and similar results observed with flavonoids rutin and quercetin (da Silva et al, ).…”

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

“…Moreover, S-phase cell cycle arrest, activation of caspases 3/7, and higher production of reactive oxygen species were demonstrated in vitro [130]. Sallem et al [131] have designed a new nanovector system for the delivery of a synthetic derivative of the RES molecule to the brain tissue, based on superparamagnetic iron oxide nanoparticles. This nanohybrid did not affect the mitochondrial metabolism, but damaged the plasma membrane of C6 glioma cells in vitro, indicating cytotoxic effects.…”

The roles of curcumin in regulating the tumor immunosuppressive microenvironment (Review)

“…Subsequently, M1 TAMs induced STAT1 and NF-κB (p65) expression, subsequently increasing the expression levels of IL-12 and thereby activating NK cells and CTLs, resulting in cytotoxicity (107). The same mechanism of action was also demonstrated in malignant glioma (108,109).…”