The continuing search for antitumor agents from higher plants

Plant secondary metabolites and their semi-synthetic derivatives continue to play an important role in anticancer drug therapy. In this short review, selected single chemical entity antineoplastic agents from higher plants that are currently in clinical trials as cancer chemotherapy drug candidates are described. These compounds are representative of a wide structural diversity. In addition, the approaches taken toward the discovery of anticancer agents from tropical plants in the laboratory of the authors are summarized. The successful clinical utilization of cancer chemotherapeutic agents from higher plants has been evident for about half a century, and, when considered with the promising pipeline of new plant-derived compounds now in clinical trials, this augurs well for the continuation of drug discovery research efforts to elucidate additional candidate substances of this type.     

Chemical Constituents and Biological Activities of Piper as Anticancer Agents: A Review

Cancer has become the primary cause of death worldwide, and anticancer drugs are used to combat this disease. Synthesis of anticancer drugs has limited success due to adverse side effects has made compounds from natural products with minimal toxicity gain much popularity. Piper species are known to have a biological effect on human health. The biological activity is due to Piper species rich with active secondary metabolites that can combat most diseases, including cancer. This review will discuss the phytochemistry of Piper species and their anticancer activity. The identification and characterization of ten active metabolites isolated from Piper species were discussed in detail and their anticancer mechanism. These metabolites were mainly found could inhibit anticancer through caspase and P38/JNK pathways. The findings discussed in this review support the therapeutic potential of Piper species against cancer due to their rich source of active metabolites with demonstrated anticancer activity.     

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis in vitro. Subsequent studies in xenograft mouse model showed that OC has anticancer potency as revealed by increased staining of cleaved CASP3, LC3 puncta, and SQSTM1, as well as reduced expression of lysosomal cathepsins. Combined treatment with OC and caloric restriction potentiates anticancer efficacy of OC in vivo. Collectively, these data demonstrated that OC is a novel autophagic flux inhibitor and might be useful in anticancer therapy.     

Microbial-based therapy of cancer: current progress and future prospects

The use of bacteria in the regression of certain forms of cancer has been recognized for more than a century. Much effort, therefore, has been spent over the years in developing wild-type or modified bacterial strains to treat cancer. However, their use at the dose required for therapeutic efficacy has always been associated with toxicity problems and other deleterious effects. Recently, the old idea of using bacteria in the treatment of cancer has attracted considerable interest and new genetically engineered attenuated strains as well as microbial compounds that might have specific anticancer activity without side effects are being evaluated for their ability to act as new anticancer agents. This involves the use of attenuated bacterial strains and expressing foreign genes that encode the ability to convert non-toxic prodrugs to cytotoxic drugs. Novel strategies also include the use of bacterial products such as proteins, enzymes, immunotoxins and secondary metabolites, which specifically target cancer cells and cause tumor regression through growth inhibition, cell cycle arrest or apoptosis induction. In this review we describe the current knowledge and discuss the future directions regarding the use of bacteria or their products, in cancer therapy.     

ω-3 Polyunsaturated fatty acids and their metabolites as inhibitors of mammalian tumorigenesis

Components of tumorigenesis include uncontrolled proliferation and defects in cell death pathways, as well as increased angiogenesis, in which tumors develop their own blood supply, and metastasis, which enables tumor dissemination. Most anticancer drugs are designed to kill cancer cells but are relatively ineffective against some phases of tumorigenesis. Alternate strategies to prevent tumorigenesis are urgently required and considerable evidence has emerged that ω-3 polyunsaturated fatty acids (PUFAs) derived from certain plants and oily fish are important modulators of tumor cell proliferation, apoptosis, angiogenesis and metastasis. Epidemiological studies in man, as well as experimental studies in animal models and cells, have reported that while ω-6 PUFA accelerate tumorigenesis, ω-3 PUFA have anticancer properties. The over-expression of certain PUFA-metabolizing enzymes in tumors, including cyclooxygenases, lipoxygenases and cytochromes P450 (CYP), has provided the impetus for studies on the roles of biotransformation products in the cancer-modulatory actions of PUFAs. Some ω-6 PUFA metabolites, including PGE₂, 5-HETE and the CYP-derived EETs, stimulate tumorigenesis by activating prostanoid receptors, nuclear receptors and intracellular signal transduction cascades. In contrast, ω-3 PUFA both inhibit the formation of pro-tumorigenic ω-6 PUFA metabolites and generate ω-3 metabolites that are anti-tumorigenic in their own right, including PGE₃ and the 17,18-epoxide of epoxyeicosapentaenoic acid (HETE). Some of these naturally occurring metabolites of ω-3 PUFA formed in human cells may be useful lead compounds for the development of novel agents that inhibit cancer.     

Studies on anticancer activities of antimicrobial peptides

In spite of great advances in cancer therapy, there is considerable current interest in developing anticancer agents with a new mode of action because of the development of resistance by cancer cells towards current anticancer drugs. A growing number of studies have shown that some of the cationic antimicrobial peptides (AMPs), which are toxic to bacteria but not to normal mammalian cells, exhibit a broad spectrum of cytotoxic activity against cancer cells. Such studies have considerably enhanced the significance of AMPs, both synthetic and from natural sources, which have been of importance both for an increased understanding of the immune system and for their potential as clinical antibiotics. The electrostatic attraction between the negatively charged components of bacterial and cancer cells and the positively charged AMPs is believed to play a major role in the strong binding and selective disruption of bacterial and cancer cell membranes, respectively. However, it is unclear why some host defense peptides are able to kill cancer cells when others do not. In addition, it is not clear whether the molecular mechanism(s) underlying the antibacterial and anticancer activities of AMPs are the same or different. In this article, we review various studies on different AMPs that exhibit cytotoxic activity against cancer cells. The suitability of cancer cell-targeting AMPs as cancer therapeutics is also discussed.     

Studies on anticancer activities of antimicrobial peptides

In spite of great advances in cancer therapy, there is considerable current interest in developing anticancer agents with a new mode of action because of the development of resistance by cancer cells towards current anticancer drugs. A growing number of studies have shown that some of the cationic antimicrobial peptides (AMPs), which are toxic to bacteria but not to normal mammalian cells, exhibit a broad spectrum of cytotoxic activity against cancer cells. Such studies have considerably enhanced the significance of AMPs, both synthetic and from natural sources, which have been of importance both for an increased understanding of the immune system and for their potential as clinical antibiotics. The electrostatic attraction between the negatively charged components of bacterial and cancer cells and the positively charged AMPs is believed to play a major role in the strong binding and selective disruption of bacterial and cancer cell membranes, respectively. However, it is unclear why some host defense peptides are able to kill cancer cells when others do not. In addition, it is not clear whether the molecular mechanism(s) underlying the antibacterial and anticancer activities of AMPs are the same or different. In this article, we review various studies on different AMPs that exhibit cytotoxic activity against cancer cells. The suitability of cancer cell-targeting AMPs as cancer therapeutics is also discussed.     

The impact of endogenous estradiol metabolites on carcinogenesis

The available literature on estrogen metabolism and estrogen metabolites involved in carcinogenesis is reviewed. Endogenous estradiol metabolism leads to metabolic products that can have various, and, to some extent, contrary, biologic effects. Thus, there are numerous research findings on the stimulation and inhibition of cancer growth by estrogen metabolites. Furthermore, there are indications that, in certain types of cancer, the production of growth-stimulating estradiol metabolites is increased. There are also reports on substances that can influence estradiol metabolism. So far, only a few estradiol metabolites have been examined with respect to their influence on the development and growth of cancer. It is presumed that other metabolites can also intervene directly or indirectly in the cancer process, but there is a great lack of research in this area. An understanding of the actions of estradiol metabolites may open up new avenues for the therapy of malignant diseases. Although little is known about the biologic effects of most of the estradiol metabolites, the reported actions of certain estradiol metabolites already justify clinical investigations on their possible beneficial uses in tumor therapy.     

WEE1 激酶及其抑制剂在抗肿瘤治疗中的应用进展

WEE1激酶是一种细胞周期调节蛋白,能调控细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1,CDK1)的磷酸化状态,从而调节CDK1与细胞周期蛋白B(cyclin B)复合物的活性从而实现对细胞周期的调控,且对DNA损伤检查点具有重要的调节作用。WEE1是G2/M期阻滞的关键基因,起着重要的监测作用,在一些癌症中过表达,抑制或下调WEE1激酶均能引发有丝分裂灾难,因此WEE1激酶抑制剂可能在抗癌治疗中有关键作用。在癌症的治疗过程中,WEE1抑制剂与DNA损伤剂、化学药物等联合使用会得到比单独使用更为有效,且在p53缺失的癌细胞中能发挥更好的效果。目前WEE1已成为许多癌症治疗的关键靶点之一,其抑制剂MK-1775已处于临床研究阶段,且能增强一些DNA损伤剂对p53缺失的癌细胞的杀伤能力。本文就WEE1激酶及其抑制剂在抗癌治疗中的应用作一综述。     

Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds.     

Recent Updates on Corals from Nephtheidae

Marine natural products display a wide range of biological activities, which play a vital role in the innovation of lead compounds for the drug development. Soft corals have been ranked at the top in regard to the discovery of bioactive metabolites with potential pharmaceutical applications. Many of the isolated cembranoids revealed diverse biological activities, such as anticancer, antidiabetic and anti‐osteoporosis. Likewise, sterols from soft corals exhibited interesting biological potential as anti‐inflammatory, antituberculosis and anticancer. Consequently, investigating marine soft corals will definitely lead to the discovery of a large number of chemically varied secondary metabolites with countless bioactivities for possible applications in medicine and pharmaceutical industry. This review provides a complete survey of all metabolites isolated from the family Nephtheidae, from 2011 until November 2018, along with their natural sources and biological potential whenever possible.     

Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery

A plethora of structurally novel bioactive secondary metabolites have been reported from the prokaryotic filamentous marine cyanobacteria in the past few decades. In addition to the production of harmful toxins, these marine blue-green algae are emerging as an important source of anticancer drugs. The majority of these potent biomolecules, including the dolastatins, curacin A, hectochlorin, the apratoxins, and the lyngbyabellins, belongs to the mixed polyketide–polypeptide structural class. Furthermore, a high proportion of these natural products target eukaryotic cytoskeleton, such as tubulin and actin microfilaments, making them an attractive source of potential anticancer drugs. In recent years, a number of potent marine cyanobacteria have also been reported to modulate cell death and apoptosis in cancer cells as well as target enzymes such as histone deacetylase. A number of marine cyanobacterial compounds have also served as structural templates for the generation of new drug leads, further attesting to the importance of these marine microbes as an important source of new pharmaceuticals. This review serves to highlight the chemistry and biology of selected anticancer marine cyanobacterial natural products exhibiting significant biological activities in the nanomolar or submicromolar range, and their discussion will be based on the different modes of action.     

Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer-signaling PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR pathway is one of the most commonly disrupted signaling pathways that plays a role in the development and pathogenicity of multiple cancers. Therefore, the critical proteins of this pathway have been targeted for anticancer therapy. The scientific community has increasingly been realizing the anti-cancer therapeutic potential of naphthoquinone analogs. These compounds constitute a major class of diverse sets of plant metabolites, which include various natural products and synthetic compounds with proven anticancer activity. The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer-signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR). The novel compound identified commonly among the top 10 dock score lists of PI3K, AKT, and mTOR was selected for further study and proposed as a potential inhibitor of the 3 cancer-signaling proteins and an anticancer agent. Further, to check the docking accuracy and potential of the compound, post docking analyses, namely, binding comparison with the native ligand, the role of the interacting residue role in binding, predicted binding energy and dissociation constant calculations, etc., were performed. All these measures showed good-quality binding, and thus provide weight to our prediction of the novel compound as a pan PI3K/AKT/mTOR inhibitor and an anticancer agent. Finally, to compare the binding and similarity in the active sites of the 3 protein kinases, a ligand-based active site alignment was performed and analyzed. Thus, the study proposed a novel naphthoquinone analog as a potential anticancer drug, and provided comparative structural insight into its binding to the 3 protein kinases.     

Persistence of Anticancer Activity in Berry Extracts after Simulated Gastrointestinal Digestion and Colonic Fermentation

Fruit and vegetable consumption is associated at the population level with a protective effect against colorectal cancer. Phenolic compounds, especially abundant in berries, are of interest due to their putative anticancer activity. After consumption, however, phenolic compounds are subject to digestive conditions within the gastrointestinal tract that alter their structures and potentially their function. However, the majority of phenolic compounds are not efficiently absorbed in the small intestine and a substantial portion pass into the colon. We characterized berry extracts (raspberries, strawberries, blackcurrants) produced by in vitro-simulated upper intestinal tract digestion and subsequent fecal fermentation. These extracts and selected individual colonic metabolites were then evaluated for their putative anticancer activities using in vitro models of colorectal cancer, representing the key stages of initiation, promotion and invasion. Over a physiologically-relevant dose range (0–50 µg/ml gallic acid equivalents), the digested and fermented extracts demonstrated significant anti-genotoxic, anti-mutagenic and anti-invasive activity on colonocytes. This work indicates that phenolic compounds from berries undergo considerable structural modifications during their passage through the gastrointestinal tract but their breakdown products and metabolites retain biological activity and can modulate cellular processes associated with colon cancer.     

我国海洋抗肿瘤药物的产业化出路

海洋富含结构新颖的抗肿瘤活性物质,已成为全世界普遍关注的研究热点。国际已上市的海洋抗肿瘤药物有阿糖胞苷(Cytarabine)、曲贝替定(Ecteinascidin-743)、甲磺酸艾日布林(Eribulin mesylate)等,还有许多源自海洋生物的抗肿瘤候选药物正在进行临床前和临床研究。我国海洋抗肿瘤物质研究成果在国际上占有相当份额,但与产业化严重脱节。通过了解国内外海洋抗肿瘤药物的研究进展和产业方向,分析了我国海洋抗肿瘤药物产业化过程存在的药源开发不足、知识产权缺乏、资金投入不足、临床周期长等问题,提出了以市场需求,多学科相互交叉为基础,产学研合作模式为主体的自主知识产权药物研究体系,从关键技术、产品市场和产业政策等方面为加速我国海洋抗肿瘤药物的产业化提供有益思考。     

Natural products for cancer chemotherapy

For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti‐tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side‐effects increase the demand for novel anti‐tumour drugs active against untreatable tumours, with fewer side‐effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti‐tumour compounds of the future.     

Hsp70 chaperone and the prospects of its application in anticancer therapy

Major stress protein Hsp70 is known to possess two important properties: ATP-dependent activity and protective activity; these two are thought to play a significant role in anticancer therapy. Many malignant tumors contain high amounts of intracellular Hsp70. Moreover, many anticancer drugs themselves are able to elevate Hsp70 expression in tumor cells. Since Hsp70 was found to disturb many signal pathways of apoptosis in many points, the high chaperone expression may lead to an increased resistance of tumor cells to anticancer drugs. On the other hand, when overexpressed by a certain mechanism, Hsp70 is able to emerge at the cell surface by itself or together with tumor antigens and present these to immune cells T-lymphocytes and natural killers, in such a manner that makes cancer cell recognized and abolished. These properties make Hsp70 very promising instrument in designing some novel anticancer vaccines.     

Engineering of bacterial strains and their products for cancer therapy

The use of live bacteria in cancer therapies offers exciting possibilities. Nowadays, an increasing number of genetically engineered bacteria are emerging in the field, with applications both in therapy and diagnosis. In parallel, purified bacterial products are also gaining relevance as new classes of bioactive products to treat and prevent cancer growth and metastasis. In the first part of the article, we review the latest findings regarding the use of live bacteria and products as anti-cancer agents, paying special attention to immunotoxins, proteins, and peptides. In particular, we focus on the recent results of using azurin or its derived peptide as anticancer therapeutic agents. In the second part, we discuss the challenges of using metagenomic techniques as a distinctive approach for discovering new anti-cancer agents from bacterial origin.     

Novel role of 3-phosphoglycerate kinase,a glycolytic enzyme,in the activation of L-nucleoside analogs,a new class of anticancer and antiviral agents

l-Nucleoside analogs are a new class of clinically active antiviral and anticancer agents. The phosphorylation of these analogs from diphosphate to triphosphate metabolites is crucial for their biological action. We studied the role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the metabolism of l-nucleoside analogs, using small interfering RNAs to down-regulate the amount of this enzyme in HelaS3 and 2.2.15 cells, chosen as models for studying the impact of the enzyme on the anticancer and antihepatitis B virus activities of these analogs. Decrease in the expression of 3-phosphoglycerate kinase led to a corresponding decrease in the formation of the triphosphate metabolites of l-nucleoside analogs (but not d-nucleoside analogs), resulting in detrimental effects on their activity. The enzyme is important for generating as well as maintaining the steady state levels of l-nucleotides in the cells, thereby playing a key role in the activity of l-nucleoside analogs against human immunodeficiency virus, hepatitis B virus, and cancer. This study also indicates a structure-based distinction in the metabolism of l- and d-nucleoside analogs, disputing the classic notion that nucleoside diphosphate kinases are responsible for the phosphorylation of all classes of nucleoside analog diphosphates.     

Molecular profiling of marine endophytic fungi from green algae: Assessment of antibacterial and anticancer activities

Bioactive natural metabolites, especially from the marine endophytic fungi, are largely unexplored. Endophytic fungi are being increasingly recognized as a group of organisms that produce novel metabolites of industrial importance. This study investigated the anticancer and antibacterial potential of the marine algal endophyte, Penicillium chrysogenum. The different organic solvent extracts of the endophytic fungi grown on different growth medium were analyzed for anticancer and antibacterial activities. The highest inhibitory activity was observed for the ethyl acetate (EA) extract of the culture filtrate grown in potato dextrose broth (PDB) for 21 days, against the tested human breast cancer cell (MCF-7) line. Similarly, the PDB-EA extract showed an appreciable activity against the human pathogens. The biochemical analysis of the Cha EA metabolites revealed terpenoids, steroids, phenolics and flavones. Gas Chromatography (GCMS) data revealed several bioactive compounds such as anthraquinone and cinnamic acid. The Cha EA extract induced membrane damage and thus, apoptosis in MCF-7cells. The secondary metabolites produced by these marine endophytic fungi have contributed to considerable anticancer and antimicrobial activities and hence, this study is an evidence of potential sources of antimicrobial and anticancer compounds from Penicillium chrysogenum.