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.

Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis.

ROS include hydroxyl radicals (HO.), superoxide (O2..), and hydrogen peroxide (H2O2). ROS are typically produced under physiological conditions and play crucial roles in living organisms. It is known that ROS, which are created spontaneously by cells through aerobic metabolism in mitochondria, can have either a beneficial or detrimental influence on biological systems. Moderate levels of ROS can cause oxidative damage to proteins, DNA and lipids, which can aid in the pathogenesis of many disorders, including cancer. However, excessive concentrations of ROS can initiate programmed cell death in cancer. Presently, a variety of chemotherapeutic drugs and herbal agents are being investigated to induce ROS-mediated cell death in cancer. Therefore, preserving ROS homeostasis is essential for ensuring normal cell development and survival. On account of a significant association of ROS levels at various concentrations with carcinogenesis in a number of malignancies, further studies are needed to determine the underlying molecular mechanisms and develop the possibilities for intervening in these processes.

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.

STAT signaling as a target for intervention: from cancer inflammation and angiogenesis to non-coding RNAs modulation.

As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions.

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Synthesis, Structural Investigations, and In Vitro/In Silico Bioactivities of Flavonoid Substituted Biguanide: A Novel Schiff Base and Its Diorganotin (IV) Complexes.

Quercetin is one of the most powerful bioactive dietary flavonoids. The in vivo biological study of quercetin is extremely difficult due to its very low solubility. However, diorganotin complexes of quercetin are more useful when contrasted with quercetin due to increased solubility. In the present study, quercetin, substituted biguanide synthesized in the form of Schiff base and its di-alkyl/aryl tin (IV) complexes were obtained by condensing Schiff base with respective di-alkyl/aryl tin (IV) dichloride. Advanced analytical techniques were used for structural elucidation. The results of biological screening against Gram-positive/Gram-negative bacteria and fungi showed that these diorganotin (IV) derivatives act as potent antimicrobial agents. The in silico investigation with dihydropteroate (DHPS) disclosed a large ligand-receptor interaction and revealed a strong relationship between the natural exercises and computational molecular docking results.

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.

Design and synthesis of novel organometallic complexes using boronated phenylalanine derivatives as potential anticancer agents.

Drug design and discovery studies are important because of the prevalence of diseases without available medical cures. New anticancer agents are particularly urgent because of the high mortality rate associated with cancer. A series of mononuclear gold (III) and platinum (II) complexes based on boronated phenylalanine (BPA) were designed and synthesized using 4,4'-dimethyl-2,2'-dipyridyl (L1) or 1,10-phenanthroline-5,6-dion (L2) ligands to obtain promising anticancer drug candidates. Proton nuclear magnetic resonance, infrared, mass spectrometry, and elemental analyses were utilized for chemical characterizations. Cell viability, cancer cell colony formation, endothelial tube formation, and cytoskeleton staining assays were performed using A549 lung adenocarcinoma and human umbilical vein endothelial cells (HUVECs) to investigate preliminary pharmacological activities. L1-based platinum (II) complex (BPA-L1-Pt) was the most promising complex, and has similar activity with the approved chemotherapy drug cis-platinum. Half maximal inhibitory concentration values for BPA-L1-Pt were 9.15 µM on A549s and 16.61 µM on HUVECs; the values for cis-platinum were 5.24 µM on A549s and 23.14 µM on HUVECs. Consequently, further synthesis studies should be performed to boost the cancer cell selectivity feature of BPA by varying metal and ligand types.

Photoprotective Activity of Vulpinic and Gyrophoric Acids Toward Ultraviolet B-Induced Damage in Human Keratinocytes.

Vulpinic and gyrophoric acids are known as ultraviolet filters for natural lichen populations because of their chemical structures. However, to the best of our knowledge, there has been no reference to their cosmetic potential for skin protection against ultraviolet B (UVB)-induced damage and, consequently, we propose to highlight their photoprotective profiles in human keratinocytes (HaCaT). Therefore, vulpinic acid and gyrophoric acid were isolated from acetone extracts of Letharia vulpina and Xanthoparmelia pokornyi, respectively. Their photoprotective activities on irradiated HaCaT cells and destructive effects on non-irradiated HaCaT cells were compared through in vitro experimentation: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, 4',6-diamino-2-phenylindole and tetramethylrhodamine B isothiocyanate-phalloidin staining protocols. Both of the lichen substances effectively prevented cytotoxic, apoptotic and cytoskeleton alterative activities of 2.5 J/cm(2) UVB in a dose-dependent manner. Moreover, vulpinic and gyrophoric acids showed no toxic, apoptotic or cytoskeleton alterative effects on non-irradiated HaCaT cells, except at high doses (≥400 µM) of gyrophoric acid. The findings suggest that vulpinic and gyrophoric acids can be promising cosmetic ingredients to photo-protect human skin cells and should therefore be further investigated by in vitro and in vivo multiple bioassays.

Polymer-mediated nanoformulations: a promising strategy for cancer immunotherapy.

Engineering polymer-based nano-systems have attracted many researchers owing to their unique qualities like shape, size, porosity, mechanical strength, biocompatibility, and biodegradability. Both natural and synthetic polymers can be tuned to get desired surface chemistry and functionalization to improve the efficacy of cancer therapy by promoting targeted delivery to the tumor site. Recent advancements in cancer immunoediting have been able to manage both primary tumor and metastatic lesions via activation of the immune system. The combinations of nano-biotechnology and immunotherapeutic agents have provided positive outcomes by enhancing the host immune response in cancer therapy. The nanoparticles have been functionalized using antibodies, targeted antigens, small molecule ligands, and other novel agents that can interact with biological systems at nanoscale levels. Several polymers, such as polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), and chitosan, have been approved by the Food and Drug Administration for clinical use in biomedicine. The polymeric nanoformulations such as polymers-antibody/antigen conjugates and polymeric drug conjugates are currently being explored as nanomedicines that can target cancer cells directly or target immune cells to promote anti-cancer immunotherapy. In this review, we focus on scientific developments and advancements on engineered polymeric nano-systems in conjugation with immunotherapeutic agents targeting the tumor microenvironment to improve their efficacy and the safety for better clinical outcomes.

Glycosylated nanoplatforms: From glycosylation strategies to implications and opportunities for cancer theranostics.

Glycosylated nanoplatforms have emerged as promising tools in the field of cancer theranostics, integrating both therapeutic and diagnostic functionalities. These nanoscale platforms are composed of different materials such as lipids, polymers, carbons, and metals that can be modified with glycosyl moieties to enhance their targeting capabilities towards cancer cells. This review provides an overview of different modification strategies employed to introduce glycosylation onto nanoplatforms, including chemical conjugation, enzymatic methods, and bio-orthogonal reactions. Furthermore, the potential applications of glycosylated nanoplatforms in cancer theranostics are discussed, focusing on their roles in drug delivery, imaging, and combination therapy. The ability of these nanoplatforms to selectively target cancer cells through specific interactions with overexpressed glycan receptors is highlighted, emphasizing their potential for enhancing efficacy and reducing the side effects compared to conventional therapies. In addition, the incorporation of diagnostic components onto the glycosylated nanoplatforms provided the capability of simultaneous imaging and therapy and facilitated the real-time monitoring of treatment response. Finally, challenges and future perspectives in the development and translation of glycosylated nanoplatforms for clinical applications are addressed, including scalability, biocompatibility, and regulatory considerations. Overall, this review underscores the significant progress made in the field of glycosylated nanoplatforms and their potential to revolutionize cancer theranostics.

Chemopreventive mechanisms of amentoflavone: recent trends and advancements.

In parallel to the continuous rise of new cancer cases all over the world, the interest of scientific community in natural anticancer agents has steadily been increased. In the past decades, numerous phytochemicals have been shown to possess a strong anticancer potential in preclinical conditions. One of such interesting compounds, derived from different plants such as ginkgo, hinoki, and St. John`s wort, is amentoflavone. In this review article, a wide range of anticancer properties of this natural biflavone are described, revealing its ability to suppress the malignant growth and lead tumor cells to apoptotic death, besides impeding also angiogenic and metastatic processes. Therefore, amentoflavone can be considered a potential lead compound for the development of novel anticancer drug candidates, definitely deserving further in vivo studies and also initiation of clinical trials. It is expected that this plant biflavone might be important, either alone or in combination with the current standard chemotherapeutics, in providing some alleviation for the continuous rise of global cancer burden.

Cytotoxic effect of eudesmanolides isolated from flowers of Tanacetum vulgare ssp. siculum.

A phytochemical analysis of the dichloromethane extract from the flowers of a subspecies of Tanacetum vulgare growing in Sicily was carried out. Five known sesquiterpene lactones with the eudesmane skeleton have been isolated and the cytotoxic activity of these compounds was tested in vitro on A549 (human lung carcinoma epithelial-like) and V79379A (Chinese hamster lung fibroblast-like) cells using the tetrazolium salt reduction (MTT) assay. All of tested compounds induced high time- and concentration-dependent cytotoxic effects.

Antimicrobial screening to molecular docking of newly synthesized ferrocenyl-substituted pyrazole.

Objective: Microbial diseases are snowballing at an alarming proportion. Therefore, the intent of this study was to inspect the antimicrobial action of ferrocenyl-substituted pyrazole against various human pathogenic Gram-positive, Gram-negative, and fungal microbial strains. Pyrazoles have been recognized for over a century as a significant and bioactive class of heterocyclic compounds. The association of pyrazoles with a ferrocene moiety may give new class of compounds. The present study was designed to synthesize biological active ferrocenyl-substituted pyrazole through a novel route. Methods: The anhydride of ferrocenyl-substituted pyrazole, namely, (S)-(3-(3-(carboxyamino)-3H-pyrazol-4-yl)cyclopenta-1,3-dien-1-yl)(cyclopenta-1,3-dien-1-yl)iron was synthesized using expansion cyclocondensation. FTIR, NMR, and GC-MS were performed to analyze the structure of the synthesized ferrocenyl-substituted pyrazole. Antimicrobial, DNA photo-cleaving, and anti-angiogenic activities of ferrocenyl-substituted compounds were studied. Results: Anhydride of (S)-(3-(3-(carboxyamino)-3H-pyrazol-4-yl)cyclopenta-1,3-dien-1-yl)(cyclopenta-1,3-dien-1-yl)iron obtained with yield of 87%. Spectral analysis confirmed the formation of anhydride. The synthesized compound was found to be biological active in the range of 85-95 µg/ml. Conclusion: This study described the novel method for the synthesis of biologically active anhydride of ferrocenyl-substituted pyrazole. The study demonstrations that synthesized ferrocenyl-substituted pyrazole in today's situation is the encouraging antimicrobial mediator against the human pathogens. In addition, it may open new doors to initiate research against drug resistance bacteria with possible biomedical applications.

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.

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.

Emodin: A metabolite that exhibits anti-neoplastic activities by modulating multiple oncogenic targets.

Oncogenic transformation has been the major cause of global mortality since decades. Despite established therapeutic regimes, majority of cancer patients either present with tumor relapse, refractory disease or therapeutic resistance. Numerous drug candidates are being explored to tap the key reason being poor tumor remission rates, from novel chemotherapy agents to immunotherapy to exploring natural compound derivatives with effective anti-cancer potential. One of these natural product metabolites, emodin has present with significant potential to target tumor oncogenic processes: induction of apoptosis and cell cycle arrest, tumor angiogenesis, and metastasis to chemoresistance in malignant cells. Based on the present scientific excerpts on safety and effectiveness of emodin in targeting hallmarks of tumor progression, emodin is being promisingly explored using nanotechnology platforms for long-term sustained treatment and management of cancer patients. In this review, we summarize the up-to-date scientific literature supporting the anti-neoplastic potential of emodin. We also provide an insight into toxicity and safety profile of emodin and how emodin has emerged as an effective therapeutic alternative in synergism with established conventional chemotherapeutic regimes for management and treatment of tumor progression.

NOTCH signaling: Journey of an evolutionarily conserved pathway in driving tumor progression and its modulation as a therapeutic target.

Notch signaling, an evolutionarily conserved signaling cascade, is critical for normal biological processes of cell differentiation, development, and homeostasis. Deregulation of the Notch signaling pathway has been associated with tumor progression. Thus, Notch presents as an interesting target for a variety of cancer subtypes and its signaling mechanisms have been actively explored from the therapeutic viewpoint. However, besides acting as an oncogene, Notch pathway can possess also tumor suppressive functions, being implicated in inhibition of cancer development. Given such interesting dual and dynamic role of Notch, in this review, we discuss how the evolutionarily conserved Notch signaling pathway drives hallmarks of tumor progression and how it could be targeted for a promising treatment and management of cancer. In addition, the up-to-date information on the inhibitors currently under clinical trials for Notch targets is presented along with how NOTCH inhibitors can be used in conjunction with established chemotherapy/radiotherapy regimes.

Photodynamic Therapy Assay.

Photodynamic therapy is a promising, minimally invasive, and clinically approved treatment strategy that destroys the cell components by oxidizing the biological molecules such as nucleic acids, carbohydrates, proteins, and lipids, and leads apoptosis in the cells of the target tissue through the generation of singlet oxygen and reactive oxygen species (ROS) owing to the synergic interactions of a nontoxic photosensitizer, a non-thermal light source, and tissue oxygen. This innovative method has drawn the attention of many scientists and been employed in a wide range of medical fields that covers the treatment of cancer diseases and precancerous dermatological disorders, and the aesthetic and cosmetic practices, including photorejuvenation and treatment of photoaging, hirsutism, facial flat warts, rosacea, acne vulgaris, and sebaceous gland hyperplasia. It was therefore intended to provide an in vitro photodynamic therapy assay protocol on human healthy keratinocytes and epidermoid carcinomas to investigate comparatively the therapeutic and destructive activities of the potent light-sensitive medications.