c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy.

BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives.

Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

Recent advances of tanshinone in regulating autophagy for medicinal research.

Initially described as an ancient and highly conserved catabolic biofunction, autophagy plays a significant role in disease pathogenesis and progression. As the bioactive ingredient of Salvia miltiorrhiza, tanshinone has recently shown profound effects in alleviating and treating various diseases by regulating autophagy. However, compared to the remarkable achievements in the known pharmacological effects of this traditional Chinese medicine, there is a lack of a concise and comprehensive review deciphering the mechanism by which tanshinone regulates autophagy for medicinal research. In this context, we concisely review the advances of tanshinone in regulating autophagy for medicinal research, including human cancer, the nervous system, and cardiovascular diseases. The pharmacological effects of tanshinone targeting autophagy involve the regulation of autophagy-related proteins, such as Beclin-1, LC3-II, P62, ULK1, Bax, ATG3, ATG5, ATG7, ATG9, and ATG12; the regulation of the PI3K/Akt/mTOR, MEK/ERK/mTOR, Beclin-1-related, and AMPK-related signaling pathways; the accumulation of reactive oxygen species (ROS); and the activation of AMPK. Notably, we found that tanshinone played a dual role in human cancers in an autophagic manner, which may provide a new avenue for potential clinical application. In brief, these findings on autophagic tanshinone and its derivatives provide a new clue for expediting medicinal research related to tanshinone compounds and autophagy.

Ellagic acid and human cancers: a systems pharmacology and docking study to identify principal hub genes and main mechanisms of action.

Research on anticancer properties of natural compounds, as effective materials that are available while causing minimal side effects, is growing. Ellagic acid (EA) is a well-known polyphenolic compound, which has been found in both free and complex modes in several medicinal plants such as pomegranate, walnut, and berries. Although many articles have reported anticancer properties for this compound, its mechanism of action has not been fully elucidated. In this study, we used several online and offline bioinformatics tools and databases to identify the mechanism of action of EA on various types of human malignancies including bladder, blood, breast, cervical, colorectal, liver, pancreas, and prostate cancers. In this context, after identifying and extracting EA-affected human genes/proteins that have been reported in various references, we built the related gene networks and determined functional hub genes. In addition, docking was performed to recognize target proteins that react directly with EA and are in fact most affected by this compound. Our findings revealed that EA exerts its anticancer effects by influencing specific hub genes in various types of cancers. Moreover, different cellular signaling pathways are affected by this natural compound. Generally, it turned out that EA probably exerts most of its anticancer activities, through induction of apoptosis, as well as P53 and WNT signaling pathways, and also by affecting the expression of several hub genes such as CDKN1A, CDK4, CDK2, CDK6, TP53, JUN, CCNA2, MAPK14, CDK1, and CCNB1 and especially interactions with some related proteins including P53, CDK6, and MAPK14.

Anticancer potential of quercetin: A comprehensive review.

Diet plays a key role to maintaining healthy life. Many natural products present in our diet, such as flavonoids, can prevent the progression of cancer. Quercetin, a distinctive bioactive flavonoid, is a dietary component that has attracted the attention of dietitians and medicinal chemists due to its numerous health-promoting effects. It is an outstanding antioxidant that has a well-documented role in reducing different human cancers. Quercetin exhibits direct proapoptotic effects on tumor cells and thus can inhibit the progress of numerous human cancers. The anticancer effect of quercetin has been documented in numerous in vitro and in vivo studies that involved several cell lines and animal models. On the other hand, the high toxic effect of quercetin against cancer cells is accompanied with little or no side effects or harm to normal cells. Accordingly, this review presents an overview of recent developments on the use of quercetin against different types of cancer along with mechanisms of action. In addition, the present review summarizes the literature pertaining to quercetin as an anticancer agent and provides an assessment of the potential utilization of this natural compound as a complimentary or alternative medicine for preventing and treating cancer.