Molecular insights into phytochemicals‐driven break function in tumor microenvironment

Abstract

Advanced knowledge about the role of tumor microenvironment (TME) in cancer progression has opened various ways to target the vast signaling pathways for cancer treatment. Failures of the currently used drugs have raised out the need to look for novel drugs which can target various crucial aspects of cancer progression (e.g., angiogenesis, uncontrolled cell division, and metastasis). Phytochemicals behaving as potent anticancer agents shows promise as therapeutics. Various phytochemicals, such as curcumin, Epigallocatechin Gallate (EGCG), resveratrol, plumbagin, genistein, and others, have been identified with modulatory effect on TME. These phytochemicals often target the molecular pathways that reside in the tumor vicinity associated with endothelial cells, cancer‐associated fibroblasts, immune cells, mesenchymal stem cells, other cell types, vascular and lymphatic networks, and extracellular matrix which are important for tumor progression and development. Some phytochemicals also target the internal signaling pathways, including STAT3, NF‐қB, ERK‐1/2, and PI3K/Akt signaling of noncancer cell, residing in the microenvironment, and thus inhibiting the supportive effect from these cells in tumor development. However, much information needs to be acquired before using these phytochemicals in cancer treatment. The primary objective of this review is to provide a better knowledge about the role of TME in cancer progression and development, focusing on the different targets which can be used for therapeutic approach, and then to give a brief account on some known phytochemicals to date, which have shown remarkable TME modulatory effects. Practical applications For the use of phytochemicals as therapeutics, it is highly recommended that their precise target should be known; therefore studies should be encouraged such that the effects of these phytochemicals can be evaluated on the individual cellular level like how the phytochemical is targeting the tumor‐associated macrophage, or any other cell residing in the tumor microenvironment (TME), and the compound should target a specific component of TME to avoid off target effects.

Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy

“…Natural products provide a rich bioactive structural base for the development of novel drugs. Some phytochemical factors affect internal signaling pathways, including STAT3, nuclear factorkappa B (NF-kB), extracellular signal-regulated kinase (ERK)-1/ 2, and phosphatidylinositol 3−kinase (PI3K)/protein kinase B (AKT) (44,45). Some natural products reportedly affect NPC progression of NPC by inhibiting STAT3 activity, including apigenin, garcinone C, b-elemene, caffeic acid phenethyl ester (CAPE), brevilin A, limonin, curcumin, wikstroflavone B, and arnicolide D.…”

Natural Product-Based Hybrids as Potential Candidates for the Treatment of Cancer: Focus on Curcumin and Resveratrol

“…The tumor microenvironment is a complex environment containing various cellular components (e.g., stromal cells, immune cells, and vascular endothelial cells), multitudinous factors (e.g., cytokines), abundant extracellular matrix (ECM), and their various cross-talk networks. Cur and Res can have modulatory effects on the tumor microenvironment [ 26 ]. In particular, Cur and Res can inhibit cancer growth through the inhibition of pathways related to epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), pro-inflammatory cytokines, and pro-inflammatory enzymes [ 27 ].…”

Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights

“…26 Mechanically, such phytochemicals also target the internal signaling pathways of the above noncancer cells, such as STAT3, NF-κB, ERK-1/2, and PI3K/Akt signaling, thereby inhibiting their supportive effect in tumor development. 26 However, despite their excellent anticancer and TME targeting abilities, phytochemicals have not been successful in clinical trials in large numbers as expected due to low bioavailability and poor pharmacokinetics. 27,28 Recently, research on nanomedicine has significantly increased globally, specifically in the field of cancer.…”

“…Recently, several investigated plant-derived secondary metabolites, such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopene, benzyl isothiocyanate, phenethyl isothiocyanate, and piperlongumine, among others, have shown potential inhibitory effects and act as chemopreventive agents against most cancer cells while not affecting normal cells. , Further, numerous phytochemicals have been found to have a modulatory effect on TME, targeting different molecular pathways associated with noncancer cells residing in the TME, such as CAFs, immune cells, CSCs, other cell types, and extracellular matrix (ECM), which are important for cancer growth and progression . Mechanically, such phytochemicals also target the internal signaling pathways of the above noncancer cells, such as STAT3, NF-κB, ERK-1/2, and PI3K/Akt signaling, thereby inhibiting their supportive effect in tumor development . However, despite their excellent anticancer and TME targeting abilities, phytochemicals have not been successful in clinical trials in large numbers as expected due to low bioavailability and poor pharmacokinetics. , …”