Regulation of micro-RNA,epigenetic factor by natural products for the treatment of cancers: Mechanistic insight and translational association

From onset to progression, cancer is a ailment that might take years to grow. All common epithelial malignancies, have a long latency period, frequently 20 years or more, different gene may contain uncountable mutations if they are clinically detectable. MicroRNAs (miRNAs) are around 22nt non-coding RNAs that control gene expression sequence-specifically through translational inhibition or messenger degradation of RNA (mRNA). Epigenetic processes of miRNA control genetic variants through genomic DNA methylation, post-translation histone modification, rework of the chromatin, and microRNAs. The field of miRNAs has opened a new era in understanding small non-coding RNAs since discovering their fundamental mechanisms of action. MiRNAs have been found in viruses, plants, and animals through molecular cloning and bioinformatics approaches. Phytochemicals can invert the epigenetic aberrations, a leading cause of the cancers of various organs, and act as an inhibitor of these changes. The advantage of phytochemicals is that they only function on cells that cause cancer without affecting normal cells. Phytochemicals appear to play a significant character in modulating miRNA expression, which is linked to variations in oncogenes, tumor suppressors, and cancer-derived protein production, according to several studies. In addition to standard anti-oxidant or anti-inflammatory properties, the initial epigenetic changes associated with cancer prevention may be modulated by many polyphenols. In correlation with miRNA and epigenetic factors to treat cancer some of the phytochemicals, including polyphenols, curcumin, resveratrol, indole-3-carbinol are studied in this article.     

Phytochemicals modulate cancer aggressiveness: A review depicting the anticancer efficacy of dietary polyphenols and their combinations

Cancer is referred to as the “Emperor of all maladies” accounting for the second-highest mortality rates worldwide. Major factors associated with cancer lethality are uncontrolled proliferation, metastasis, and frequent recurrence. The conventional therapeutic drugs used in cancer therapy have been associated with numerous damaging side-effects that call for the use of alternative therapeutic options. The natural plant compounds (NPCs) have been found to be effective against diverse groups of diseases including cancer. Among the different types, the polyphenolic phytochemicals like curcumin, (−)epigallocatechin-3-gallate, Resveratrol, and nimbolide which are predominant parts of daily dietary intake have proved their potency in reducing the aggressive properties of cancer. Here, we have highlighted the mechanisms through which these NPCs influence growth, metastatic potential, and the drug-resistant behavior of different cancer types. Moreover, we have also emphasized on their function as modulators of the immune system as well as the metabolic properties of the tumor. The role of these phytochemicals in reducing cancer progression has been highlighted when administered unaided or in combination with similar group of compounds. Moreover, their ability to enhance the drug-sensitivity of cancer cells which accounts for their use in combination with conventional chemotherapeutics has also been discussed in this article. Therefore, co-administration of these phytochemicals with chemically similar group members or with conventional chemotherapeutics may prove to be an effective treatment strategy for cancer.     

Protection against chemotherapy- and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals

BackgroundAlthough great achievements have been made in the field of cancer therapy, chemotherapy and radiotherapy remain the mainstay cancer therapeutic modalities. However, they are associated with various side effects, including cardiocytotoxicity, nephrotoxicity, myelosuppression, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, mucositis, and alopecia, which severely affect the quality of life of cancer patients. Plants harbor a great chemical diversity and flexible biological properties that are well-compatible with their use as adjuvant therapy in reducing the side effects of cancer therapy.PurposeThis review aimed to comprehensively summarize the molecular mechanisms by which phytochemicals ameliorate the side effects of cancer therapies and their potential clinical applications.MethodsWe obtained information from PubMed, Science Direct, Web of Science, and Google scholar, and introduced the molecular mechanisms by which chemotherapeutic drugs and irradiation induce toxic side effects. Accordingly, we summarized the underlying mechanisms of representative phytochemicals in reducing these side effects.ResultsRepresentative phytochemicals exhibit a great potential in reducing the side effects of chemotherapy and radiotherapy due to their broad range of biological activities, including antioxidation, antimutagenesis, anti-inflammation, myeloprotection, and immunomodulation. However, since a majority of the phytochemicals have only been subjected to preclinical studies, clinical trials are imperative to comprehensively evaluate their therapeutic values.ConclusionThis review highlights that phytochemicals have interesting properties in relieving the side effects of chemotherapy and radiotherapy. Future studies are required to explore the clinical benefits of these phytochemicals for exploitation in chemotherapy and radiotherapy.     

β-catenin-mediated signaling: A novel molecular target for chemoprevention with anti-inflammatory substances

Inflammation is thought to play a role in the pathophysiology of cancer. Accumulating evidence from clinical and laboratory-based studies suggests that substances with anti-inflammatory activities are potential candidates for chemoprevention. Recent advances in cellular and molecular biology of cancer shed light on components of intracellular signaling cascades that can be potential molecular targets of chemoprevention with various anti-inflammatory substances. Although cyclooxygenase-2, a primary enzyme that mediates inflammatory responses, has been well recognized as a molecular target for chemoprevention by both synthetic and natural anti-inflammatory agents, the cellular signaling mechanisms that associate inflammation and cancer are not still clearly illustrated. Recent studies suggest that β-catenin-mediated signaling, which regulates developmental processes, may act as a potential link between inflammation and cancer. This review aims to focus on β-catenin-mediated signaling pathways, particularly in relation to its contribution to carcinogenesis, and the modulation of inappropriately activated β-catenin-mediated signaling by nonsteroidal anti-inflammatory drugs and chemopreventive phytochemicals possessing anti-inflammatory properties.     

beta-Catenin-mediated signaling: a novel molecular target for chemoprevention with anti-inflammatory substances

Inflammation is thought to play a role in the pathophysiology of cancer. Accumulating evidence from clinical and laboratory-based studies suggests that substances with anti-inflammatory activities are potential candidates for chemoprevention. Recent advances in cellular and molecular biology of cancer shed light on components of intracellular signaling cascades that can be potential molecular targets of chemoprevention with various anti-inflammatory substances. Although cyclooxygenase-2, a primary enzyme that mediates inflammatory responses, has been well recognized as a molecular target for chemoprevention by both synthetic and natural anti-inflammatory agents, the cellular signaling mechanisms that associate inflammation and cancer are not still clearly illustrated. Recent studies suggest that beta-catenin-mediated signaling, which regulates developmental processes, may act as a potential link between inflammation and cancer. This review aims to focus on beta-catenin-mediated signaling pathways, particularly in relation to its contribution to carcinogenesis, and the modulation of inappropriately activated beta-catenin-mediated signaling by nonsteroidal anti-inflammatory drugs and chemopreventive phytochemicals possessing anti-inflammatory properties.     

Influence of phytochemicals on the biocompatibility of inorganic nanoparticles: a state-of-the-art review

Inorganic nanoparticles (NPs) are among the most produced NPs that could be used in consumer products and as healthcare materials, however, the intrinsic toxicity particularly through the mechanism associated oxidative stress raises the health concern about inorganic NP exposure. Phytochemicals are bioactive metabolites derived from plants as well as non-pathogenic microorganisms living within plants and have been shown to be beneficial to human health with their anti-aging, anti-cancer, anti-inflammation and anti-oxidant properties. In the present review, the influence of on the biocompatibility of inorganic NPs was discussed. It has been shown that phytochemicals could be used as bio-friendly capping agents for green synthesis of inorganic NPs, and phytochemical coated inorganic NPs were remarkable stable and biocompatible with high therapeutic efficiency. Meanwhile, the presence of phytochemicals was also able to reduce the side effects and enhance the therapeutic abilities of inorganic NPs, which is likely attributed to the anti-oxidative properties of phytochemicals. Thus, using phytochemicals could be a promising and plausible way to reduce side effects and increase the biocompatibility of inorganic NPs for biomedical applications.     

Inhibition of cytokine-induced prostanoid biogenesis by phytochemicals in human colonic fibroblasts

Many of the inflammatory pathways regulating the production of prostanoids are implicated in the development of colon cancer. Diets rich in fruits and vegetables are associated with decreased rates of colon cancer and this may reflect anti-inflammatory properties of some phytochemicals in plant-based foods. In order to ascertain which of the many dietary compounds may be protective, a cell-based screening method was established to determine their effects on the production of prostanoids. By up-regulating prostaglandin H synthase-2 in human colonic fibroblast cells with cytokines, we have investigated the potential protective effect of a structurally related group of phytochemicals on prostanoid biogenesis. Several of the compounds significantly inhibited prostanoid biogenesis, by up to 81% and others enhanced prostanoid production. All of the compounds that enhanced prostanoid production belonged to the hydroxylated benzoic acid family and good correlation was observed with their redox activity and the ability to enhance prostanoid production. Common structural features of the inhibitors were the presence of 4-hydroxyl and 3-methoxyl substituents on the aromatic ring and/or the presence of a three-carbon side-chain on C1.     

Artemisia: a promising plant for the treatment of cancer

Due to the promising features of the ancient herbal plant Artemisia, its biologic activity has been investigated for use in modern medicine. In this regard, Artemisia and its active phytochemicals have been introduced as having antimalarial, antioxidant, cytotoxic, antispasmodic, anthelmintic, neuroprotective, anti-inflammatory, and antimicrobial agents. In the case of cancer treatment, the plant species and its bioactive compounds target multiple pathways. Here we reviewed the scientific literature published up until 2018, which have explained the cytotoxic activity of the Artemisia species and their constituents. This review summarizes the published data found in PubMed, Science Direct and Scopus. Here, studies about the cytotoxicity and antitumor action on cancer cells and tumor bearing animals are discussed. Also, detailed molecular pathways affected by the plant and the phytochemistry of the cytotoxic active components are presented. Among all species and chemical constituents, the active ones have been selected and discussed in detail. The cytotoxic comparison made here may open a window for future works and selection of agents for cancer chemotherapy.     

Nutritional antioxidants and adaptive cell responses: an update

Many plant antioxidants, intaken through the daily diet or plant-derived dietary supplements, have been shown able to prevent free radical-related diseases by counteracting cell oxidative stress. However, it is now considered that the in vivo beneficial effects of these phytochemicals are unlikely to be explained just by their antioxidant capability. Several plant antioxidants exhibit hormetic properties, by acting as 'low-dose stressors' that may prepare cells to resist more severe stress. In fact, low doses of these phytochemicals activate cell signaling pathways (being the most prominent examples the modulation of the Nrf2/Keap1 pathway, the NF-κB pathway and the Sirtuin-FOXO pathway) but high doses are cytotoxic. Herein we review the adaptive responses induced by the most known plant hormetic antioxidants, which are sulforaphane, resveratrol, curcumin, flavonoids, green tea catechins and diallylsulphides, as well as the molecular mechanisms involved in such responses. Furthermore, this review outlines that the hormetic properties of these bioactive plant antioxidants might be successfully employed for realizing health-promoting dietary interventions especially in the field of neurodegenerative diseases and cancer.     

Chemistry and pharmacology of oxyprenylated secondary plant metabolites

Oxyprenylated natural products (isopentenyloxy-, geranyloxy- and the less spread farnesyloxy- compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been considered for years just as biosynthetic intermediates of C-prenylated derivatives. Only in the last decade these natural products have been recognized as interesting and valuable biologically active phytochemicals. Up to now about 300 molecules have been isolated from plants mainly belonging to the families of Rutaceae and Compositae, comprising common edible vegetables and fruits. A wide variety of compounds containing a prenyloxy side chain have been isolated and these comprise alkaloids, coumarins, flavonoids, cinnamic acids, benzoic acids, phenols, alcohols, aldehydes, anthraquinones, chalcones, lignans, xanthones, aceto- and benzophenones and other more uncommon skeletons. Many of the isolated oxyprenylated natural products and their semisynthetic derivatives were shown to exert in vitro and in vivo remarkable anti-cancer, anti-inflammatory, anti-microbial and anti-fungal effects. The aim of this review is to examine in detail the different types of oxyprenylated natural compounds from a phytochemical and pharmacological point of view.     

Osteopontin-c splicing isoform contributes to ovarian cancer progression

Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression.     

Monocyte and interferon based therapy for the treatment of ovarian cancer

Cytokines and cells of the innate immune system have been shown to be critical regulators in the elimination, equilibrium and escape of malignant cells. Despite in vitro and in vivo evidence, components of the innate immune system have shown limited efficacy in the treatment of ovarian cancer. Intraperitoneal immunotherapies are a promising field that has not yet been fully explored in ovarian cancer. Cytokine immunotherapy using interferon alpha (IFN-α) and interferon gamma (IFN-γ) has predominantly been used intraperitoneally in ovarian cancer, with promising results. Early studies also showed that autologous monocytes infused into the peritoneum have anti-tumor properties. Combination therapies have been shown to be more effective in treating cancer than mono-therapies. Based on these observations the combination of cell therapy with cytokine therapy may provide a unique strategy for the treatment of chemotherapy resistant solid cancers.     

Therapeutic potential of monoacylglycerol lipase inhibitors

Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown beneficial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid–eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.     

Green tea prevents non-melanoma skin cancer by enhancing DNA repair

Excessive exposure of the skin to solar ultraviolet (UV) radiation is one of the major factors for the development of skin cancers, including non-melanoma. For the last several centuries the consumption of dietary phytochemicals has been linked to numerous health benefits including the photoprotection of the skin. Green tea has been consumed as a popular beverage world-wide and skin photoprotection by green tea polyphenols (GTPs) has been widely investigated. In this article, we have discussed the recent investigations and mechanistic studies which define the potential efficacy of GTPs on the prevention of non-melanoma skin cancer. UV-induced DNA damage, particularly the formation of cyclobutane pyrimidine dimers, has been implicated in immunosuppression and initiation of skin cancer. Topical application or oral administration of green tea through drinking water of mice prevents UVB-induced skin tumor development, and this prevention is mediated, at least in part, through rapid repair of DNA. The DNA repair by GTPs is mediated through the induction of interleukin (IL)-12 which has been shown to have DNA repair ability. The new mechanistic investigations support and explain the anti-photocarcinogenic activity, in particular anti-non-melanoma skin cancer, of green tea and explain the benefits of green tea for human health.     

Retinoids and ovarian cancer

Each year, an estimated 26,000 women in the United States are diagnosed with ovarian cancer. During any given year, approximately 14,500 women die from this disease. Ovarian cancer is the seventh most common cancer in women worldwide, after breast, cervix, colon/rectum, stomach, corpus uteri, and lung cancers. In the U.S., ovarian cancer is the second most common gynecologic cancer, and is the fourth leading cause of solid tumor cancer deaths among women. Currently, postoperative chemotherapy of ovarian cancer is still suboptimal. Drug resistance is a common problem resulting in only 20 approximately 30% overall 5-year survival rates. Clearly, continued development of alternative therapeutic strategies is essential for the management of this fatal disease. A number of recent studies have suggested that retinoids may play a potential role as an ovarian cancer chemotherapeutic agent. Retinoids, the natural and synthetic derivatives of vitamin A, have been shown to inhibit the growth of human ovarian cancer cells both in vivo and in culture. This review will initially summarize what is known about the pathological and molecular characteristics of ovarian carcinoma. It will then describe retinoid metabolism and the role of the cellular and nuclear retinoid binding proteins in mediating retinoid action. Following this general review of retinoids and their function, data supporting the role of retinoic acid as a suppresser of ovarian carcinoma cell growth will be presented. Particular attention will be paid to studies suggesting that members of the RB family of proteins and RB2/p130, in particular, are the molecular targets responsible for retinoid mediated inhibition of ovarian carcinoma cell growth. This review will then conclude with a brief discussion of two synthetic retinoids, 4 HPR R(fenretinide) and AHPN/CD437, which have been shown to induce apoptosis in ovarian tumor cells. It will be clear from the studies summarized in this review that retinoids represent a potentially powerful alternative to present chemotherapeutic approaches to the treatment of late stage ovarian cancer.