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Natural Compounds as Metabolic Modulators
The tumor microenvironment (TME) comprises a heterogenous assemblage of malignant and non-malignant cells, including infiltrating immune cells and other stromal cells, together with extracellular matrix and a variety of soluble factors. This complex and dynamic milieu strongly affects tumor differentiation, progression, immune evasion, and response to therapy, thus being an important therapeutic target. The phenotypic and functional features of the various cell types present in the TME are largely dependent on their ability to adopt different metabolic programs. Hence, modulating the metabolism of the cells in the TME, and their metabolic crosstalk, has emerged as a promising strategy in the context of anticancer therapies. Natural compounds offer an attractive tool in this respect as their multiple biological activities can potentially be harnessed to ‘(re)-educate’ TME cells towards antitumoral roles.
2. Metabolic Modulation of TME Cells by Natural Compounds
2.3. Epigallocatechin Gallate
Shikonin (Figure 1e) is a naturally occurring naphthoquinone found in the root of plants from the Boraginaceae family and the first compound to be obtained from large-scale plant cell cultures . It has been used in traditional Chinese medicine for centuries and shown to possess several therapeutic properties, including antimicrobial, wound healing, anti-inflammatory, antioxidant, and anticancer activities . The potential of shikonin and its derivatives in cancer treatment has received increasing attention in recent years, mainly due to its wide spectrum antitumor effects . Repression of glycolysis through specific inhibition of PKM2, the enzyme catalyzing the conversion of phosphoenolpyruvate to pyruvate, is a key mechanism in shikonin’s antitumor activity, as demonstrated in a variety of tumor cells .
Recent data clearly showed that shikonin-mediated metabolic effects impacted the TME by repolarizing TAM and synergizing with PD-1 blockage (mediated by JQ1), thus enhancing the immune response . In that work, mannosylated lactoferrin nanoparticles were loaded with shikonin (1 μM) and JQ1 (3 μM), for targeted codelivery to colon cancer cells (CT26) and TAM. The bioactive NPs reduced lactate production in cancer cells (in association with PKM2-mediated glycolytic inhibition), and skewed macrophages towards a pro- inflammatory phenotype, characterized by higher production of TNF-α and lower secretion of TGF-β. Furthermore, treatment of CT26-tumor-bearing mice with the shikonin/JQ1-loaded nanosystem efficiently decreased tumor growth, suppressed glucose metabolism (as seen by reduced levels of lactate, PKM2 and HIF-1α in the tumor tissue), downregulated intratumoral PD-L1 expression, and remodeled the TME’s immune configuration (e.g., promotion of dendritic cell maturation and CD8+ T cell infiltration, as well as suppression of Treg). Overall, the synergism between metabolic reprogramming and regulation of immune responses was shown to improve antitumor treatment efficacy.
The entry is from 10.3390/molecules26123494
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