Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement.

Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed.

Path of Silibinin from diet to medicine: A dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance.

In the last few decades, targeting cancer by the use of dietary phytochemicals has gained enormous attention. The plausible reason and believe or mind set behind this fact is attributed to either lesser or no side effects of natural compounds as compared to the modern chemotherapeutics, or due to their conventional use as dietary components by mankind for thousands of years. Silibinin is a naturally derived polyphenol (a flavonolignans), possess following biochemical features; molecular formula C25H22O10, Molar mass: 482.44 g/mol, Boiling point 793 °C, with strikingly high antioxidant and anti-tumorigenic properties. The anti-cancer properties of Silibinin are determined by a variety of cellular pathways which include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis and metastasis. In addition, Silibinin controls modulation of the expression of aberrant miRNAs, inflammatory response, and synergism with existing anti-cancer drugs. Therefore, modulation of a vast array of cellular responses and homeostatic aspects makes Silibinin an attractive chemotherapeutic agent. However, like other polyphenols, the major hurdle to declare Silibinin a translational chemotherapeutic agent, is its lesser bioavailability. After summarizing the chemistry and metabolic aspects of Silibinin, this extensive review focuses on functional aspects governed by Silibinin in chemoprevention with an ultimate goal of summarizing the evidence supporting the chemopreventive potential of Silibinin and clinical trials that are currently ongoing, at a single platform.

Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling.

Despite the immense therapeutic advances in the field of health sciences, cancer is still to be found among the global leading causes of morbidity and mortality. Ethnomedicinally, natural bioactive compounds isolated from various plant sources have been used for the treatment of several cancer types and have gained notable attention. Ferulic acid, a natural compound derived from various seeds, nuts, leaves, and fruits, exhibits a variety of pharmacological effects in cancer, including its proapoptotic, cell-cycle-arresting, anti-metastatic, and anti-inflammatory activities. This review study presents a thorough overview of the molecular targets and cellular signaling pathways modulated by ferulic acid in diverse malignancies, showing high potential for this phenolic acid to be developed as a candidate agent for novel anticancer therapeutics. In addition, current investigations to develop promising synergistic formulations are also discussed.

Deguelin targets multiple oncogenic signaling pathways to combat human malignancies.

Cancer is an anomalous growth and differentiation of cells known to be governed by oncogenic factors. Plant-based natural metabolites have been well recognized to possess chemopreventive properties. Deguelin, a natural rotenoid, is among the class of bioactive phytoconstituents from a diverse range of plants with potential antineoplastic effects in different cancer subtypes. However, the precise mechanisms of how deguelin inhibits tumor progression remains elusive. Deguelin has shown promising results in targeting the hallmarks of tumor progression via inducing tumor apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis. Based on initial scientific excerpts, deguelin has been reported to inhibit tumor growth via different signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, serine/threonine protein kinase B (also known as Akt), mammalian target of rapamycin, nuclear factor-κB, matrix metalloproteinase (MMP)-2, MMP-9 and caspase-3, caspase-8, and caspase-9. This review summarizes the mechanistic insights of antineoplastic action of deguelin to gain a clear understanding of its therapeutic effects in cancer. The anticancer potential of deguelin with respect to its efficacy in targeting tumorigenesis via nanotechnological approaches is also investigated. The initial scientific findings have presented deguelin as a promising antitumorigenic agent which can be used for monotherapy as well as synergistically to augment efficacy of chemotherapeutic treatment regimes.

Advancements and recent explorations of anti-cancer activity of chrysin: from molecular targets to therapeutic perspective.

In recent times, there have been notable advancements in comprehending the potential anti-cancer effects of chrysin (CH), a naturally occurring flavonoid compound found abundantly in various plant sources like honey, propolis, and certain fruits and vegetables. This active compound has garnered significant attention due to its promising therapeutic qualities and minimal toxicity. CH's ability to combat cancer arises from its multifaceted mechanisms of action, including the initiation of apoptosis and the inhibition of proliferation, angiogenesis, metastasis, and cell cycle progression. CH also displays potent antioxidant and anti-inflammatory properties, effectively counteracting the harmful molecules that contribute to DNA damage and the development of cancer. Furthermore, CH has exhibited the potential to sensitize cancer cells to traditional chemotherapy and radiotherapy, amplifying the effectiveness of these treatments while reducing their negative impact on healthy cells. Hence, in this current review, the composition, chemistry, mechanisms of action, safety concerns of CH, along with the feasibility of its nanoformulations. To conclude, the recent investigations into CH's anti-cancer effects present a compelling glimpse into the potential of this natural compound as a complementary therapeutic element in the array of anti-cancer approaches, providing a safer and more comprehensive method of combating this devastating ailment.

Luteolin: A promising modulator of apoptosis and survival signaling in liver cancer.

Due to the increasing incidence of cancer and the difficulties in determining the safety profile of existing therapeutic approaches, cancer research has recently become heavily involved in the search for new therapeutic approaches. The therapeutic significance of natural substances, especially flavonoids, against the onset and progression of cancer has been emphasized in traditional food-based medicine. Interestingly, the flavone luteolin possesses biological effects that have been linked to its anti-inflammatory, antioxidant, and anticancer effects. Luteolin interacts with several downstream chemicals and signaling pathways, including those involved in apoptosis, autophagy, cell cycle progression, and angiogenesis, to exert its anticancer effects on various cancerous cells. A complete understanding of both intrinsic and extrinsic apoptotic pathways, autophagy, and, most critically, the nanodelivery of luteolin in liver cancer is provided in the current review.

Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements.

Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and is regarded as an excellent free-radical scavenger. Apoptotic cell death of cancer cells caused by quercetin has been demonstrated by many prior studies. It is present in many fruits, vegetables, and herbs. Quercetin targets apoptosis, by upregulating Bax, caspase-3, and p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, and Bcl-2. Additionally, it has been reported to increase STAT3 protein degradation in liver cancer cells while decreasing STAT3 activation. Quercetin has a potential future in chemoprevention, based on substantial research on its anticancer effects. The current review discusses quercetin's mechanisms of action, nanodelivery strategies, and other potential cellular effects in liver cancer.

Wogonin, as a potent anticancer compound: From chemistry to cellular interactions.

Chinese native medicine Scutellaria baicalensis Georgi, also referred to as Chinese skullcap or Huang-Qin, is frequently used to treat cancer, viral infections, and seizures. This plant's abundance of flavones (wogonoside) and their related aglycones (wogonin) is responsible for many of its pharmacologic effects. A significant ingredient in S. baicalensis that has been the subject of the most research is wogonin. Numerous preclinical investigations revealed that wogonin suppresses tumor growth by cell cycle arrest, stimulating cell death and preventing metastasis. This review focuses on a complete overview of published reports that suggest chemopreventive action of wogonin and the mechanistic insights behind these neoplastic activities. It also emphasizes the synergistic improvements made by wogonin in chemoprevention. The factual data in this mini-review stimulate additional research on chemistry and toxicological profile of wogonin to confirm its safety issues. This review will encourage researchers to generalize the merits of wogonin to be used as potential compound for cancer treatment.

Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models.

BACKGROUND: Melittin is a water-soluble cationic peptide derived from bee venom that has been thoroughly studied for the cure of different cancers. However, the unwanted interactions of melittin produce hemolytic and cytotoxic effects that hinder their therapeutic applications. To overcome the shortcomings, numerous research groups have adopted different approaches, including conjugation with tumor-targeting proteins, gene therapy, and encapsulation in nanoparticles, to reduce the non-specific cytotoxic effects and potentiate their anti-cancerous activity. PURPOSE: This article aims to provide mechanistic insights into the chemopreventive activity of melittin and its nanoversion in combination with standard anti-cancer drugs for the treatment of cancer. METHODS: We looked over the pertinent research on melittin's chemopreventive properties in online databases such as PubMed and Scopus. CONCLUSION: In the present article, the anti-cancerous effects of melittin on different cancers have been discussed very nicely, as have their possible mechanisms of action to act against different tumors. Besides, it interacts with different signal molecules that regulate the diverse pathways of cancerous cells, such as cell cycle arrest, apoptosis, metastasis, angiogenesis, and inflammation. We also discussed the recent progress in the synergistic combination of melittin with standard anti-cancer drugs and a nano-formulated version of melittin for targeted delivery to improve its anticancer potential.

Hepatoprotective effects of natural drugs: Current trends, scope, relevance and future perspectives.

BACKGROUND: The liver is a well-known player in the metabolism and removal of drugs. Drug metabolizing enzymes in the liver detoxify drugs and xenobiotics, ultimately leading to the acquisition of homeostasis. However, liver toxicity and cell damage are not only related to the nature and dosage of a particular drug but are also influenced by other factors such as aging, immune status, environmental contaminants, microbial metabolites, gender, obesity, and expression of individual genes Furthermore, factors such as drugs, alcohol, and environmental contaminants could induce oxidative stress, thereby impairing the regenerative potential of the liver and causing several diseases. Persons suffering from other ailments and those with comorbidities are found to be more prone to drug-induced toxicities. Moreover, drug composition and drug-drug interactions could further aggravate the risk of drug-induced hepatotoxicity. A plethora of mechanisms are responsible for initiating liver cell damage and further aggravating liver cell injury, followed by impairment of homeostasis, ultimately leading to the generation of reactive oxygen species, immune-suppression, and oxidative stress. OBJECTIVE: To summarize the potential of phytochemicals and natural bioactive compounds to treat hepatotoxicity and other liver diseases. STUDY DESIGN: A deductive qualitative content analysis approach was employed to assess the overall outcomes of the research and review articles pertaining to hepatoprotection induced by natural drugs, along with analysis of the interventions. METHODS: An extensive literature search of bibliographic databases, including Web of Science, PUBMED, SCOPUS, GOOGLE SCHOLAR, etc., was carried out to understand the role of hepatoprotective effects of natural drugs. RESULTS: Bioactive natural products, including curcumin, resveratrol, etc., have been seen as neutralizing agents against the side effects induced by the drugs. Moreover, these natural products are dietary and are readily available; thus, could be supplemented along with drugs to reduce toxicity to cells. Probiotics, prebiotics, and synbiotics have shown promise of improving overall liver functioning, and these should be evaluated more extensively for their hepatoprotective potential. Therefore, selecting an appropriate natural product or a bioactive compound that is free of toxicity and offers a reliable solution for drug-induced liver toxicity is quintessential. CONCLUSIONS: The current review highlights the role of natural bioactive products in neutralizing drug-induced hepatotoxicity. Efforts have been made to delineate the possible underlying mechanism associated with the neutralization process.

Nanoformulations of quercetin for controlled delivery: a review of preclinical anticancer studies.

One of the well-studied older molecules, quercetin, is found in large quantities in many fruits and vegetables. Natural anti-oxidant quercetin has demonstrated numerous pharmacological properties in preclinical and clinical research, including anti-inflammatory and anti-cancer effects. Due to its ability to control cell signaling pathways, including NF-κB, p53, activated protein-1 (AP-1), STAT3, and epidermal growth response-1 (Egr-1), which is essential in the initiation and proliferation of cancer, it has gained a lot of fame as an anticancer molecule. Recent research suggests that using nanoformulations can help quercetin to overcome its hydrophobicity while also enhancing its stability and cellular bioavailability both in vitro and in vivo. The main aim of this review is to focus on the comprehensive insights of several nanoformulations, including liposomes, nano gels, micelles, solid lipid nanoparticles (SLN), polymer nanoparticles, gold nanoparticles, and cyclodextrin complexes, to transport quercetin for application in cancer.

Genistein: a promising modulator of apoptosis and survival signaling in cancer.

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.

Anticancer potential of oroxylin A: from mechanistic insight to synergistic perspectives.

Oroxylin A (OA), a well-known constituent of the root of Scutellariae plants, has been used in ethnomedicine already for centuries in treating various neoplastic disorders. However, only recent molecular studies have revealed the different mechanisms behind its action, demonstrating antiproliferative, anti-inflammatory, and proapoptotic effects, restricting also the spread of cancer cells to distant organs. A variety of cellular targets and modulated signal transduction pathways regulated by OA have been determined in diverse cells derived from different malignant tissues. In this review article, these anticancer activities are thoroughly described, representing OA as a potential lead structure for the design of novel more potent anticancer medicines. In addition, co-effects of this natural compound with conventional anticancer agents are analyzed and the advantages provided by nanotechnological methods for more efficient application of OA are discussed. In this way, OA might represent an excellent example of using ethnopharmacological knowledge for designing modern medicines.

Gallic Acid: A Dietary Polyphenol that Exhibits Anti-neoplastic Activities by Modulating Multiple Oncogenic Targets.

Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.

Galangin: A metabolite that suppresses anti-neoplastic activities through modulation of oncogenic targets.

With the dramatic increase in cancer incidence all over the world in the last decades, studies on identifying novel efficient anti-cancer agents have been intensified. Historically, natural products have represented one of the most important sources of new lead compounds with a wide range of biological activities. In this article, the multifaceted anti-cancer action of propolis-derived flavonoid, galangin, is presented, discussing its antioxidant, anti-inflammatory, antiproliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic effects in various cancer cells. In addition, co-effects with standard chemotherapeutic drugs as well as other natural compounds are also under discussion, besides highlighting modern nanotechnological advancements for overcoming the low bioavailability issue characteristic of galangin. Although further studies are needed for confirming the anti-cancer potential of galangin in vivo malignant systems, exploring this natural compound might open new perspectives in molecular oncology.

Cucurbitacins as Potent Chemo-Preventive Agents: Mechanistic Insight and Recent Trends.

Cucurbitacins constitute a group of cucumber-derived dietary lipids, highly oxidized tetracyclic triterpenoids, with potential medical uses. These compounds are known to interact with a variety of recognized cellular targets to impede the growth of cancer cells. Accumulating evidence has suggested that inhibition of tumor cell growth via induction of apoptosis, cell-cycle arrest, anti-metastasis and anti-angiogenesis are major promising chemo-preventive actions of cucurbitacins. Cucurbitacins may be a potential choice for investigations of synergism with other drugs to reverse cancer cells' treatment resistance. The detailed molecular mechanisms underlying these effects include interactions between cucurbitacins and numerous cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R, etc.) as well as control of a variety of intracellular signal transduction pathways. The current study is focused on the efforts undertaken to find possible molecular targets for cucurbitacins in suppressing diverse malignant processes. The review is distinctive since it presents all potential molecular targets of cucurbitacins in cancer on one common podium.

Gut Microbiota-Assisted Synthesis, Cellular Interactions and Synergistic Perspectives of Equol as a Potent Anticancer Isoflavone.

It is well known that, historically, plants have been an important resource of anticancer agents, providing several clinically approved drugs. Numerous preclinical studies have shown a strong anticancer potential of structurally different phytochemicals, including polyphenolic constituents of plants, flavonoids. In this review article, suppressing effects of equol in different carcinogenesis models are unraveled, highlighting the mechanisms involved in these anticancer activities. Among flavonoids, daidzein is a well-known isoflavone occurring in soybeans and soy products. In a certain part of population, this soy isoflavone is decomposed to equol under the action of gut microflora. Somewhat surprisingly, this degradation product has been shown to be more bioactive than its precursor daidzein, revealing a strong and multifaceted anticancer potential. In this way, it is important to bear in mind that the metabolic conversion of plant flavonoids might lead to products that are even more efficient than the parent compounds themselves, definitely deserving further studies.

Licorice (Glycyrrhiza glabra L.)-Derived Phytochemicals Target Multiple Signaling Pathways to Confer Oncopreventive and Oncotherapeutic Effects.

Cancer is a highly lethal disease, and its incidence has rapidly increased worldwide over the past few decades. Although chemotherapeutics and surgery are widely used in clinical settings, they are often insufficient to provide the cure for cancer patients. Hence, more effective treatment options are highly needed. Although licorice has been used as a medicinal herb since ancient times, the knowledge about molecular mechanisms behind its diverse bioactivities is still rather new. In this review article, different anticancer properties (antiproliferative, antiangiogenic, antimetastatic, antioxidant, and anti-inflammatory effects) of various bioactive constituents of licorice (Glycyrrhiza glabra L.) are thoroughly described. Multiple licorice constituents have been shown to bind to and inhibit the activities of various cellular targets, including B-cell lymphoma 2, cyclin-dependent kinase 2, phosphatidylinositol 3-kinase, c-Jun N-terminal kinases, mammalian target of rapamycin, nuclear factor-κB, signal transducer and activator of transcription 3, vascular endothelial growth factor, and matrix metalloproteinase-3, resulting in reduced carcinogenesis in several in vitro and in vivo models with no evident toxicity. Emerging evidence is bringing forth licorice as an anticancer agent as well as bottlenecks in its potential clinical application. It is expected that overcoming toxicity-related obstacles by using novel nanotechnological methods might importantly facilitate the use of anticancer properties of licorice-derived phytochemicals in the future. Therefore, anticancer studies with licorice components must be continued. Overall, licorice could be a natural alternative to the present medication for eradicating new emergent illnesses while having just minor side effects.

Luteolin, a Potent Anticancer Compound: From Chemistry to Cellular Interactions and Synergetic Perspectives.

Increasing rates of cancer incidence and the toxicity concerns of existing chemotherapeutic agents have intensified the research to explore more alternative routes to combat tumor. Luteolin, a flavone found in numerous fruits, vegetables, and herbs, has exhibited a number of biological activities, such as anticancer and anti-inflammatory. Luteolin inhibits tumor growth by targeting cellular processes such as apoptosis, cell-cycle progression, angiogenesis and migration. Mechanistically, luteolin causes cell death by downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2, and Bcl-xL, while upregulating BAX, caspase-3, and p21. It has also been reported to inhibit STAT3 signaling by the suppression of STAT3 activation and enhanced STAT3 protein degradation in various cancer cells. Therefore, extensive studies on the anticancer properties of luteolin reveal its promising role in chemoprevention. The present review describes all the possible cellular interactions of luteolin in cancer, along with its synergistic mode of action and nanodelivery insight.

Xanthohumol: A Metabolite with Promising Anti-Neoplastic Potential.

The overwhelming global burden of cancer has posed numerous challenges and opportunities for developing anti-cancer therapies. Phytochemicals have emerged as promising synergistic compounds with potential anti-cancer effects to supplement chemo- and immune-therapeutic regimens. Anti cancer synergistic effects have been investigated in the interaction between phytocompounds derived from flavonoids such as quercetin, apigenin, kaempferol, hesperidin, emodin, etc., and conventional drugs. Xanthohumol is one of the prenylated phytoflavonoid that has demonstrated key anti-cancer activities in in vitro (anti proliferation of cancer cell lines) and in vivo (animal models of xenograft tumours) studies, and has been explored from different dimensions for targeting cancer subtypes. In the last decade, xanthohumol has been investigated how it induces the anti- cancer effects at cellular and molecular levels. The different signalling cascades and targets of xanthohumol are summarized in this review. Overall, this review summarizes the current advances made in the field of natural compounds with special reference to xanthohumol and its promising anti-cancer effects to inhibit tumour progression. The present review has also discussedthe potential of xanthohumol transitioning into a leadingcandidate from nano-therapy viewpoint along with the challenges which need to be addressed for extensive preclinical and clinical anti-cancer studies.