Current Medicinal Chemistry (v.20, #7)

As the incidence of skin tumors has been steadily growing, there is an urgent need for the preventive measures as well as the improved therapeutic approaches. In the last two decades, natural plant derived polyphenols (PPs, resveratrol, silibinin, green tea polyphenols, flavonoids, anthocyanins, etc.) have been drawing particular interest as emerging active substances in dermatological/ cosmeceutical compositions for the prevention, slowing, or reversion of skin tumorigenesis (chemoprevention). When chronically applied to the skin, they supposedly would not damage normal skin cells or negatively affect their functions while they would suppress tumorigenic cell transformation, inhibit tumor cell proliferation, and activate tumor cell apoptosis. PPs are also reported to synergize with conventional anti-cancer therapies. The major aim of this critical review is to provide recent updates on the molecular and cellular targets for the prevention and therapy of skin tumors with a special focus on the crossroad between inflammation and carcinogenesis as the most promising approach to chemoprevention. Novel therapeutic targets as different as epidermal stem cells, cellular senescence, epigenetic enzymes involved in carcinogenesis, epidermal growth factor and aryl hydrocarbon receptors, and metabolic CYP1 subfamily enzymes are highlighted. The mechanisms of PPs interaction with these molecular and cellular targets are reviewed. The feasibility of PPs to prevent/ cure specific cutaneous toxicity connected to anti-EGFR therapy and to reduce multidrug resistance of skin tumors is also discussed.

Modulation of Human Keratinocyte Responses to Solar UV by Plant Polyphenols As a Basis for Chemoprevention of Non-Melanoma Skin Cancers by V.A. Kostyuk, A.I. Potapovich, D. Lulli, A. Stancato, C. De Luca, S. Pastore, L. Korkina (869-879).
Excessive exposure to solar UVA and UVB radiation is widely considered to cause skin cancers such as squamous cell carcinoma and basalioma. Direct UVB damage to skin cell DNA as well as UV-induced chronic skin inflammation, accelerated keratinocyte proliferation, inhibited apoptosis, and immunosuppression seem to underlie the UV-induced carcinogenesis. Also, UVB induces cytochrome P450 subfamilies (CYP1A1 and CYP1B1) involved in metabolic activation of organic pro-carcinogens and their conversion to ultimate carcinogens. Here, the effects of several glycosylated and non-glycosylated plant polyphenols (verbascoside, resveratrol, polydatin, rutin, and quercetin) on the inflammatory, apoptotic, metabolic, and proliferative responses of cultured human epidermal keratinocytes (HEK) to non-cytotoxic doses of solar-simulated UVA+UVB and chemical mediators of UV signalling in HEK, 6- formylindolo[3,2-b]carbazole and squalene isolated from photo-oxidized skin surface lipids (SSL), were evaluated. We showed that the stilbenes and quercetin being exposed to UV were photo-destroyed within a short period of time, while verbascoside and rutin were photo-stable. When SSL were exposed to UV, the stilbenes and quercetin remarkably accelerated photo-oxidation of alpha-tocopherol, squalene, and cholesterol fractions, whilst verbascoside protected them. Verbascoside invariably inhibited molecular pathways in HEK leading to inflammatory cytokine expression (NFkappaB and EGFR/ERK phosphorylation), and cell proliferation (EGFR nuclear translocation), and displayed a stimulus-specific effect on the metabolic axis aryl hydrocarbon receptor (AhR)-CYP1A1/CYP1B1. By contrast, the stilbenes inhibited UV-connected inflammatory cytokines excluding IL-8, but they prevalently stimulated NFkappaB, EGFR nuclear translocation and the AhR-CYP pathway. We conclude that, among the PPs investigated, verbascoside does interfere with multiple UV-sensitive signalling in HEK in a way that it could have a major impact on skin cancer chemoprevention.

Bioprocessing of Plant In Vitro Systems for the Mass Production of Pharmaceutically Important Metabolites: Paclitaxel and its Derivatives by M. Onrubia, R.M. Cusido, K. Ramirez, L. Hernandez-Vazquez, E. Moyano, M. Bonfill, J. Palazon (880-891).
Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of “omics” tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the fluxlimiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production.

Nitrogen-containing bioactive alkaloids of plant origin play a significant role in human health and medicine. Several semisynthetic antimitotic alkaloids are successful in anticancer drug development. Gloriosa superba biosynthesizes substantial quantities of colchicine, a bioactive molecule for gout treatment. Colchicine also has antimitotic activity, preventing growth of cancer cells by interacting with microtubules, which could lead to the design of better cancer therapeutics. Further, several colchicine semisynthetics are less toxic than colchicine. Research is being conducted on effective, less toxic colchicine semisynthetic formulations with potential drug delivery strategies directly targeting multiple solid cancers. This article reviews the dynamic state of anticancer drug development from colchicine semisynthetics and natural colchicine production and briefly discusses colchicine biosynthesis.

Natural Cures for Type 1 Diabetes: A Review of Phytochemicals, Biological Actions, and Clinical Potential by C.L.T. Chang, Yi-Ching Chen, Hui-Ming Chen, Ning-Sun Yang, Wen-Chin Yang (899-907).
Autoimmune diseases are the third largest category of illness in the industrialized world, following cardiovascular diseases and cancers. Among them, type 1 diabetes, also named autoimmune diabetes, afflicts 10 million people worldwide. This disease is caused by autoimmunity-mediated destruction of pancreatic β-cells, leading to insulin deficiency, hyperglycemia and complications. Currently, there is no cure for type 1 diabetes. Insulin injection is the only medication; however, it accompanies serious medical complications. Current strategies to cure type 1 diabetes include immunotherapy, replacement therapy, and combination therapy. Despite recent advances in anti-diabetic strategies, no strategy is clinically successful. How to cure type 1 diabetes without undesirable side effects still remains a formidable challenge in drug research and development. Plants provide an extraordinary source of natural medicines for different diseases. Moreover, secondary metabolites of plant origin serve as an invaluable chemical library for drug discovery and current medicinal chemistry in the pharmaceutical industry. Over the past 25 years, 50% of prescription drugs have been developed from natural products and their derivatives. In this article, we review more than 20 plant compounds and extracts reported in the literature to prevent and treat type-1 diabetes. Emphasis is placed on their chemistry and biology in terms of regulation of immune cells and pancreatic β-cells. We summarize recent progress in understanding the biological actions, mechanisms and therapeutic potential of the compounds and extracts of plant origin in type 1 diabetes. New views on phytocompound-based strategies for prevention and treatment of type 1 diabetes are also discussed.

The Pentacyclic Triterpenoids in Herbal Medicines and Their Pharmacological Activities in Diabetes and Diabetic Complications by A. Alqahtani, K. Hamid, A. Kam, K.H. Wong, Z. Abdelhak, V. Razmovski-Naumovski, K. Chan, K.M. Li, P.W. Groundwater, G.Q. Li (908-931).
Pentacyclic triterpenoids including the oleanane, ursane and lupane groups are widely distributed in many medicinal plants, such as Glycyrrhiza species, Gymnema species, Centella asiatica, Camellia sinensis, Crataegus species and Olea europaea, which are commonly used in traditional medicine for the treatment of diabetes and diabetic complications. A large number of bioactive pentacyclic triterpenoids, such as oleanolic acid, glycyrrhizin, glycyrrhetinic acid, ursolic acid, betulin, betulinic acid and lupeol have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion, diabetic vascular dysfunction, retinopathy and nephropathy. The versatility of the pentacyclic triterpenes provides a promising approach for diabetes management.

Antimicrobial Plant Metabolites: Structural Diversity and Mechanism of Action by N.S. Radulovic, P.D. Blagojevic, Z.Z. Stojanovic-Radic, N.M. Stojanovic (932-952).
Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality. It has been estimated that microbial species comprise about 60% of the Earth's biomass. This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world. Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems. Thus, the need to discover and develop new antimicrobial agents is critical to improve mankind's future health. Plant secondary metabolites (PSMs) offer particular promise in this sense. Plant Kingdom could be considered a rich source of the most diverse structures (e.g. there are more than 12,000 known alkaloids, more than 8,000 phenolic compounds and over 25,000 different terpenoids), many of which were proven to possess strong antimicrobial properties (e.g. thymol, eurabienol, etc.). In many instances, PSMs can be easily isolated from the plant matrix, either in pure state or in the form of mixtures of chemically related compounds. What is also important is that the development of bacterial resistance toward natural plant products (that are generally regarded as eco-friendly) has been thus far documented in a very limited number of cases (e.g. for reserpine). Having all of the mentioned advantages of PSMs as potential antimicrobials in mind, a major question arises: why is it that there are still no commercially available or commonly used antibiotics of plant origin? This review tries to give a critical answer to this question by considering potential mechanisms of antimicrobial action of PSMs (inhibition of cell wall or protein synthesis, inducing leakage from the cells by tampering with the function of the membranes, interfering with intermediary metabolisms or DNA/RNA synthesis/function), as well as their physical and chemical properties (e.g. hydrophilicity/lipophilicity, chemical stability). To address the possible synergistic/antagonistic effects between PSMs and with standard antibiotics, special attention has been given to the antimicrobial activity of PSM-mixtures (e.g. essential oils, plant extracts). Moreover, possible ways of overcoming some of PSMs molecular limitations in respect to their usage as potential antibiotics were also discussed (e.g. derivatization that would enable fine tuning of certain molecular characteristics).

Marine Natural Products with Anti-HIV Activities in the Last Decade by Xuefeng Zhou, Juan Liu, Bin Yang, Xiuping Lin, Xian-Wen Yang, Yonghong Liu (953-973).
Marine organisms have been proven to be excellent sources of biologically active compounds against HIV. This review gives an overview of 132 natural products from marine sources obtained during the last decade (2002–2011), which exhibit anti-HIV activity toward different biological targets. Sponges contribute more than half of all anti-HIV natural products from marine organisms, mainly as alkaloids and cyclic depsipeptides. In addition, some macromolecules are considered as potential anti-HIV agents, including lectins from algae and marine invertebrates, as well as sulfated polysaccharides from algae. In the reviewed marine natural products, many active ingredients act as HIV entry inhibitors, one class of new anti-HIV agents, and may be regarded as potential candidates for the development of novel anti-HIV agents. The other features of development in the marine original anti-HIV natural products in this ten years are also discussed.