Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

Abstract

BackgroundTumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance.ObjectivesThis is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy.MethodsA comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals.ResultsPhytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted.ConclusionTargeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.

Targeting Triple-Negative Breast Cancer by the Phytopolyphenol Carnosol: ROS-Dependent Mechanisms

“…Several phytochemicals have been reported to display anticancer activity against cancer, including TNBC, such as resveratrol, indole-3-carbino, fisetin, 6-gingerol, curcumin, capsaicin, quercetin, ursolic acid, ailanthone, and cordycepin [25][26][27][28][29][30][31]. These phytochemicals reportedly target several molecular pathways implicated in carcinogenesis, including apoptosis, proliferation, inflammation, invasion, metastasis, angiogenesis, and chemoresistance [25][26][27][28][29][30][31].…”

Targeting transforming growth factor‐ß signalling for cancer prevention and intervention: Recent advances in developing small molecules of natural origin

“… 26 , 27 , 28 Out of the various other pathways, some prominent therapeutic targets for plant secondary metabolites are the mammalian target of rapamycin (mTOR), phosphatidylinositol 3‐kinases (PI3K), protein kinase B (or Akt), hypoxia‐inducible factor‐1α (HIF‐1α) and extracellular signal‐regulated kinase (ERK), 29 nuclear factor‐κB (NF‐κB), activator protein 1, 30 c‐Jun NH 2 ‐terminal kinases (JNKs), mitogen‐activated protein kinase (MAPK), tumour necrosis factor (TNF) receptor‐associated factor (TRAF), TNF receptor 1‐associated death domain protein, Janus kinase (JAK) and the signal transducer and activator of transcription (STAT). 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 …”

“…[26][27][28] Out of the various other pathways, some prominent therapeutic targets for plant secondary metabolites are the mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinases (PI3K), protein kinase B (or Akt), hypoxiainducible factor-1α (HIF-1α) and extracellular signalregulated kinase (ERK), 29 nuclear factor-κB (NF-κB), activator protein 1, 30 c-Jun NH 2 -terminal kinases (JNKs), mitogen-activated protein kinase (MAPK), tumour necrosis factor (TNF) receptor-associated factor (TRAF), TNF receptor 1-associated death domain protein, Janus kinase (JAK) and the signal transducer and activator of transcription (STAT). [26][27][28][29][30][31][32][33][34][35] The transforming growth factor-β (TGF-ß) signalling pathway plays a crucial role in various cellular responses; misregulation of this pathway often leads to tumour progression. 36 The regulatory cytokine TGF-ß has tumoursuppressive effects, which can be evaded by cancer cells through malignant evolution.…”

“…Various phytoconstituents have gained special attention and provided a novel avenue for cancer treatment through targeting different cross‐linked pathways, such as oxidative stress, mutagenesis, inflammation, apoptosis and autophagy, as well as several signalling intermediaries, including cancer metabolism 26–28 . Out of the various other pathways, some prominent therapeutic targets for plant secondary metabolites are the mammalian target of rapamycin (mTOR), phosphatidylinositol 3‐kinases (PI3K), protein kinase B (or Akt), hypoxia‐inducible factor‐1α (HIF‐1α) and extracellular signal‐regulated kinase (ERK), 29 nuclear factor‐κB (NF‐κB), activator protein 1, 30 c‐Jun NH 2 ‐terminal kinases (JNKs), mitogen‐activated protein kinase (MAPK), tumour necrosis factor (TNF) receptor‐associated factor (TRAF), TNF receptor 1‐associated death domain protein, Janus kinase (JAK) and the signal transducer and activator of transcription (STAT) 26–35 …”

Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus

“…Cancer is the uncontrolled growth of cells and formation of tumors caused by genetic changes, and in recent decades, it has been considered to be one of the major causes of death in the world [ 1 , 2 ]. Genetic disorders, exposure to variant physical and chemical agents, tobacco, radiation, infections, environmental pollutants, obesity, and diet are some of the important risk factors for cancer [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Cancerous cells have a variety of basic origins and pathologies, such as aberrant cell cycles, proliferation, apoptosis, and angiogenesis [ 8 , 9 ].…”