Marine Natural Products with P-Glycoprotein Inhibitor Properties

P-glycoprotein (P-gp) is a protein belonging to the ATP-binding cassette (ABC) transporters superfamily that has clinical relevance due to its role in drug metabolism and multi-drug resistance (MDR) in several human pathogens and diseases. P-gp is a major cause of drug resistance in cancer, parasitic diseases, epilepsy and other disorders. This review article aims to summarize the research findings on the marine natural products with P-glycoprotein inhibitor properties. Natural compounds that modulate P-gp offer great possibilities for semi-synthetic modification to create new drugs and are valuable research tools to understand the function of complex ABC transporters.     

Current Status on Marine Products with Reversal Effect on Cancer Multidrug Resistance

The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR) is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp), ABCC1/multidrug resistance protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP). These transporters are part of the ATP-binding cassette (ABC) superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker) and cyclosporin A (immunosuppressive agent), etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones.     

Lamellarin O,a Pyrrole Alkaloid from an Australian Marine Sponge,Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells

ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1–12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure–activity relationship analysis inclusive of the natural products 1–12 and the synthetic analogues 13–19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.     

Marine Antitumor Peptide Dolastatin 10: Biological Activity,Structural Modification and Synthetic Chemistry

Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC₅₀ = 0.03 nM), small cell lung cancer NCI-H69 cells (IC₅₀ = 0.059 nM), and human prostate cancer DU-145 cells (IC₅₀ = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris^®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides.     

Development of Marine-Derived Compounds for Cancer Therapy

Cancer has always been a threat to human health with its high morbidity and mortality rates. Traditional therapy, including surgery, chemotherapy and radiotherapy, plays a key role in cancer treatment. However, it is not able to prevent tumor recurrence, drug resistance and treatment side effects, which makes it a very attractive challenge to search for new effective and specific anticancer drugs. Nature is a valuable source of multiple pharmaceuticals, and most of the anticancer drugs are natural products or derived from them. Marine-derived compounds, such as nucleotides, proteins, peptides and amides, have also shed light on cancer therapy, and they are receiving a fast-growing interest due to their bioactive properties. Their mechanisms contain anti-angiogenic, anti-proliferative and anti-metastasis activities; cell cycle arrest; and induction of apoptosis. This review provides an overview on the development of marine-derived compounds with anticancer properties, both their applications and mechanisms, and discovered technologies.     

Anticancer Activities of Plant Secondary Metabolites: Rice Callus Suspension Culture as a New Paradigm

Plant natural products including alkaloids,polyphenols,terpenoids and flavonoids have been reported to exert anticancer activity by targeting various metabolic pathways.The biological pathways regulated by plant products can serve as novel drug targets.Plant natural compounds or their derivatives used for cancer treatment and some novel plant-based compounds which are used in clinical trials were discussed.Callus suspension culture with secondary metabolites can provide a continuous source of plant pharmaceuticals without time and space limitations.Previous research has shown that rice callus suspension culture can kill>95%cancer cells with no significant effect on the growth of normal cells.The role of candidate genes and metabolites which are likely to be involved in the process and their potential to serve as anticancer and anti-inflammatory agents were discussed.Large scale production of plant callus suspension culture and its constituents can be achieved using elicitors which enhance specific secondary metabolites combined with bioprocess technology.     

Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine

Breast cancer is the leading cause of death among women worldwide. Over the years, oxidative stress has been linked to the onset and progression of cancer. In addition to the classical histological classification, breast carcinomas are classified into phenotypes according to hormone receptors (estrogen receptor—RE—/progesterone receptor—PR) and growth factor receptor (human epidermal growth factor receptor—HER2) expression. Luminal tumors (ER/PR-positive/HER2-negative) are present in older patients with a better outcome. However, patients with HER2-positive or triple-negative breast cancer (TNBC) (ER/PR/HER2-negative) subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Therefore, new alternative therapies have become an urgent clinical need. In recent years, anticancer agents based on natural products have been receiving huge interest. In particular, carotenoids are natural compounds present in fruits and vegetables, but algae, bacteria, and archaea also produce them. The antioxidant properties of carotenoids have been studied during the last years due to their potential in preventing and treating multiple diseases, including cancer. Although the effect of carotenoids on breast cancer during in vitro and in vivo studies is promising, clinical trials are still inconclusive. The haloarchaeal carotenoid bacterioruberin holds great promise to the future of biomedicine due to its particular structure, and antioxidant activity. However, much work remains to be performed to draw firm conclusions. This review summarizes the current knowledge on pre-clinical and clinical analysis on the use of carotenoids as chemopreventive and chemotherapeutic agents in breast cancer, highlighting the most recent results regarding the use of bacterioruberin from haloarchaea.     

Marine Power on Cancer: Drugs,Lead Compounds,and Mechanisms

Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest biosphere of the earth that harbors a great many different organisms and natural products, to identify novel drugs and drug candidates to fight against malignant neoplasms. The marine compounds show potent anticancer activity in vitro and in vivo, and relatively few drugs have been approved by the U.S. Food and Drug Administration for the treatment of metastatic malignant lymphoma, breast cancer, or Hodgkin′s disease. This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives.     

Modification of Marine Natural Product Ningalin B and SAR Study Lead to Potent P-Glycoprotein Inhibitors

In this study, new marine ningalin B analogues containing a piperazine or a benzoloxy group at ring C have been synthesized and evaluated on their P-gp modulating activity in human breast cancer and leukemia cell lines. Their structure-activity relationship was preliminarily studied. Compounds 19 and 20 are potent P-gp inhibitors. These two synthetic analogues of permethyl ningalin B may be potentially used as effective modulators of P-gp-mediated drug resistance in cancer cells.     

Long lasting rubber tree resistance to Microcyclus ulei characterized by reduced conidial emission and absence of teleomorph

The resistance of the MDF 180 Hevea brasiliensis cultivar to South American leaf blight caused by Microcyclus ulei has been studied under both controlled conditions of inoculation, and under natural infestation in the Brazilian state of Bahia. Inoculated isolates on this cultivar in most cases developed sporulating lesions and produced conidiospores, but at a moderate level, characteristic of a race non-specific, partial resistance. The teleomorph of M. ulei has never been reported on this cultivar, either in controlled conditions or in natural infestation, whereas it is commonly observed on other susceptible cultivars. This type of resistance has seldom been described for other pathosystems. MDF 180 resistance having also endured for more than 30 years in areas very conducive to the disease can, therefore, be described as a durable resistance. Rubber productivity of this cultivar is not sufficient to allow planting on industrial scale, but its resistance characteristics make it a good progenitor candidate for rubber tree resistance breeding programs.     

Marine Bromophenol Bis(2,3,6-Tribromo-4,5-Dihydroxybenzyl)ether Inhibits Angiogenesis in Human Umbilical Vein Endothelial Cells and Reduces Vasculogenic Mimicry in Human Lung Cancer A549 Cells

Angiogenesis, including the growth of new capillary blood vessels from existing ones and the malignant tumors cells formed vasculogenic mimicry, is quite important for the tumor metastasis. Anti-angiogenesis is one of the significant therapies in tumor treatment, while the clinical angiogenesis inhibitors usually exhibit endothelial cells dysfunction and drug resistance. Bis(2,3,6-tribromo-4,5-dihydroxybenzyl)ether (BTDE), a marine algae-derived bromophenol compound, has shown various biological activities, however, its anti-angiogenesis function remains unknown. The present study illustrated that BTDE had anti-angiogenesis effect in vitro through inhibiting human umbilical vein endothelial cells migration, invasion, tube formation, and the activity of matrix metalloproteinases 9 (MMP9), and in vivo BTDE also blocked intersegmental vessel formation in zebrafish embryos. Moreover, BTDE inhibited the migration, invasion, and vasculogenic mimicry formation of lung cancer cell A549. All these results indicated that BTDE could be used as a potential candidate in anti-angiogenesis for the treatment of cancer.     

Fucoidan Structure and Its Impact on Glucose Metabolism: Implications for Diabetes and Cancer Therapy

Fucoidans are complex polysaccharides derived from brown seaweeds which consist of considerable proportions of L-fucose and other monosaccharides, and sulphated ester residues. The search for novel and natural bioproduct drugs (due to toxicity issues associated with chemotherapeutics) has led to the extensive study of fucoidan due to reports of it having several bioactive characteristics. Among other fucoidan bioactivities, antidiabetic and anticancer properties have received the most research attention in the past decade. However, the elucidation of the fucoidan structure and its biological activity is still vague. In addition, research has suggested that there is a link between diabetes and cancer; however, limited data exist where dual chemotherapeutic efforts are elucidated. This review provides an overview of glucose metabolism, which is the central process involved in the progression of both diseases. We also highlight potential therapeutic targets and show the relevance of fucoidan and its derivatives as a candidate for both cancer and diabetes therapy.     

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home to much of the planet’s biodiversity. Biodiversity is directly related to chemodiversity, which can inspire new drug discoveries. Therefore, natural products (NPs) in general, and MNPs in particular, have been used for decades as a source of inspiration for the design of new drugs. However, NPs present both opportunities and challenges. These difficulties can be technical, such as the need to dive or trawl to collect the organisms possessing the compounds, or biological, due to their particular marine habitats and the fact that they can be uncultivable in the laboratory. For all these difficulties, the contributions of CADD can play a very relevant role in simplifying their study, since, for example, no biological sample is needed to carry out an in-silico analysis. Therefore, the amount of natural product that needs to be used in the entire preclinical and clinical study is significantly reduced. Here, we exemplify how this combination between CADD and MNPs can help unlock their therapeutic potential. In this study, using a set of marine invertebrate molecules, we elucidate their possible molecular targets and associated therapeutic potential, establishing a pipeline that can be replicated in future studies.     

Antimicrobial Compounds from Eukaryotic Microalgae against Human Pathogens and Diseases in Aquaculture

The search for novel compounds of marine origin has increased in the last decades for their application in various areas such as pharmaceutical, human or animal nutrition, cosmetics or bioenergy. In this context of blue technology development, microalgae are of particular interest due to their immense biodiversity and their relatively simple growth needs. In this review, we discuss about the promising use of microalgae and microalgal compounds as sources of natural antibiotics against human pathogens but also about their potential to limit microbial infections in aquaculture. An alternative to conventional antibiotics is needed as the microbial resistance to these drugs is increasing in humans and animals. Furthermore, using natural antibiotics for livestock could meet the consumer demand to avoid chemicals in food, would support a sustainable aquaculture and present the advantage of being environmentally friendly. Using natural and renewable microalgal compounds is still in its early days, but considering the important research development and rapid improvement in culture, extraction and purification processes, the valorization of microalgae will surely extend in the future.     

柱花草种质抗寒性评价与筛选

柱花草是全球热带地区栽培面积最大、应用最广泛的优良豆科牧草，其在生产上的主要限制性因素是越冬性 差、怕霜冻，因此筛选柱花草抗寒材料显得尤为重要。本研究从海南冬季自然条件下田间栽培的 350 份柱花草资源中， 根据株高、叶绿素等形态和生理指标筛选出 9 份长势相对较好的柱花草材料，在不同低温条件下（4 ℃和?18 ℃）胁 迫不同时间，以叶绿素、丙二醛、相对电导率为抗寒性评价指标，并通过隶属函数分析，得出 CIAT1433 西卡柱花草 和热研 20 号圭亚那柱花草抗寒性较强，可作为亚热带地区冬季的推广品种或首选抗寒柱花草育种材料。     

Antiviral lead compounds from marine sponges

Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hoped to be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.     

晶须与偶联剂改性大豆蛋白胶黏剂

选用硅烷偶联剂KH560作为改性剂,对碳酸钙晶须进行表面改性.研究了经KH560改性的碳酸钙晶须对大豆分离蛋白(SPI)胶黏剂粘接性能和耐水性的影响,考察了KH560用量和碳酸钙晶须用量对胶黏体系性能的影响.利用万能试验机测试对胶黏剂体系的剪切强度进行了测试,借助差示扫描量热仪(DSC)对胶黏剂热性能进行了分析.结果表明:当KH560用量为4%(wt)、碳酸钙晶须用量为2%(wt)、SPI含量为10%(-at)时体系的粘接性能和耐水性最好,与未改性SPI胶黏剂相比,干剪切强度提高了28.88%,浸泡后剪切强度提高了71.41%,湿剪切强度提高了76.68%;变性温度与未改性SPI胶黏剂相比有所下降.此外,利用FYIR和光学显微镜对体系内部结构进行了表征.     

Ginsenoside Rp1 from <Emphasis Type="Italic">Panax ginseng</Emphasis> Exhibits Anti-cancer Activity by Down-regulation of the IGF-1R/Akt Pathway in Breast Cancer Cells

Cancer prevention is effective and reduces health care costs because cancer is often a preventable disease that can be affected by lifestyle factors. Therefore, researchers are interested in discovering natural compounds that have anticancer activities, such as delaying the development of cancer and preventing its progression. One such natural agent is ginseng (Panax ginseng), which is traditionally used in some parts of the world as a popular remedy for various diseases including cancer. We hypothesized that the ginsenoside Rp1, a component of ginseng, reduces cancer cell proliferation through inhibition of the insulin-like growth factor 1 receptor (IGF-1R)/Akt pathway. We first tested the efficacy of Rp1 against human breast cancer cell lines. Treatment with Rp1 inhibited breast cancer cell proliferation and inhibited both anchorage-dependent and -independent breast cancer cell colony formation. In addition, treatment with 20 μM Rp1 induced cycle arrest and apoptosis-mediated cell growth suppression. Our findings further indicated that Rp1 decreased the stability of the IGF-1R protein in breast cancer cells. Therefore, we suggest that Rp1 has potential as an anticancer drug and that IGF-1R is an important target for treatment and prevention of breast cancer.