Anticancer Natural Products Research Articles

Hyperthermia Treatment as a Promising Anti-Cancer Strategy: Therapeutic Targets, Perspective Mechanisms and Synergistic Combinations in Experimental Approaches.

Despite recent developments in diagnosis and treatment options, cancer remains one of the most critical threats to health. Several anti-cancer therapies have been identified, but further research is needed to provide more treatment options that are safe and effective for cancer. Hyperthermia (HT) is a promising treatment strategy for cancer because of its safety and cost-effectiveness. This review summarizes studies on the anti-cancer effects of HT and the detailed mechanisms. In addition, combination therapies with anti-cancer drugs or natural products that can effectively overcome the limitations of HT are reviewed because HT may trigger protective events, such as an increase of heat shock proteins (HSPs). In the 115 reports included, the mechanisms related to apoptosis, cell cycle, reactive oxygen species, mitochondrial membrane potential, DNA damage, transcription factors and HSPs were considered important. This review shows that HT is an effective inducer of apoptosis. Moreover, the limitations of HT may be overcome using combined therapy with anti-cancer drugs or natural products. Therefore, appropriate combinations of such agents with HT will exert maximal effects to treat cancer.

Deoxyelephantopin and Its Isomer Isodeoxyelephantopin: Anti-Cancer Natural Products with Multiple Modes of Action

Cancer is a leading cause of morbidity and mortality worldwide. The development of cancer involves aberrations in multiple pathways, representing promising targets for anti-cancer drug discovery. Natural products are regarded as a rich source for developing anti-cancer therapies due to their unique structures and favorable pharmacology and toxicology profiles. Deoxyelephantopin and isodeoxyelephantopin, sesquiterpene lactone compounds, are major components of Elephantopus scaber and Elephantopus carolinianus, which have long been used as traditional medicines to treat multiple ailments, including liver diseases, diabetes, bronchitis, fever, diarrhea, dysentery, cancer, renal disorders, and inflammation-associated diseases. Recently, deoxyelephantopin and isodeoxyelephantopin have been extensively explored for their anti-cancer activities. This review summarizes and discusses the anti-cancer activities of deoxyelephantopin and isodeoxyelephantopin, with an emphasis on their modes of action and molecular targets. Both compounds disrupt several processes involved in cancer progression by targeting multiple signaling pathways deregulated in cancers, including cell cycle and proliferation, cell survival, autophagy, and invasion pathways. Future directions of research on these two compounds towards anti-cancer drug development are discussed.

Nuciferine Inhibits TMEM16A in Dietary Adjuvant Therapy for Lung Cancer.

Lung cancer is a malignant tumor with the highest morbidity and mortality rates. Food therapy is a common adjuvant treatment for lung cancer due to its safety and painlessness. Developing new functional food and exploring novel drug targets is important for lung cancer adjuvant therapy. This study confirmed that the active ingredient nuciferine of the lotus leaf was a novel TMEM16A inhibitor by whole-cell patch clamp experiments and site-directed mutagenesis experiments. CCK8 assay, colony formation assay, wound healing assay, and Annexin-V assay were combined to prove that nuciferine inhibited the proliferation and migration of lung cancer cells and promoted cancer cell apoptosis by targeting TMEM16A. Moreover, the combination of nuciferine and cisplatin significantly enhanced the anti-cancer effect of cisplatin. In addition, the signal transduction pathway of nuciferine regulating LA795 cell proliferation, migration, and apoptosis was confirmed by western blot experiments. In vivo experiments showed that nuciferine was a safe and effective natural anti-cancer product for lung cancer. Tissue section pathological detection and pharmacokinetic experiments verified that intragastric administration of nuciferine significantly enhanced the cancer therapy effect of cisplatin and counteracted the toxicity of high concentrations of cisplatin. Therefore, nuciferine is an ideal functional food for adjuvant lung cancer treatment.

IANP-EC: Identifying Anticancer Natural Products Using Ensemble Learning Incorporated with Evolutionary Computation.

Cancer is one of the most deadly diseases that annually kills millions of people worldwide. The investigation on anticancer medicines has never ceased to seek better and more adaptive agents with fewer side effects. Besides chemically synthetic anticancer compounds, natural products are scientifically proved as a highly potential alternative source for anticancer drug discovery. Along with experimental approaches being used to find anticancer drug candidates, computational approaches have been developed to virtually screen for potential anticancer compounds. In this study, we construct an ensemble computational framework, called iANP-EC, using machine learning approaches incorporated with evolutionary computation. Four learning algorithms (k-NN, SVM, RF, and XGB) and four molecular representation schemes are used to build a set of classifiers, among which the top-four best-performing classifiers are selected to form an ensemble classifier. Particle swarm optimization (PSO) is used to optimise the weights used to combined the four top classifiers. The models are developed by a set of curated 997 compounds which are collected from the NPACT and CancerHSP databases. The results show that iANP-EC is a stable, robust, and effective framework that achieves an AUC-ROC value of 0.9193 and an AUC-PR value of 0.8366. The comparative analysis of molecular substructures between natural anticarcinogens and nonanticarcinogens partially unveils several key substructures that drive anticancerous activities. We also deploy the proposed ensemble model as an online web server with a user-friendly interface to support the research community in identifying natural products with anticancer activities.

A Complexed Crystal Structure of a Single-Stranded DNA-Binding Protein with Quercetin and the Structural Basis of Flavonol Inhibition Specificity.

Single-stranded DNA (ssDNA)-binding protein (SSB) plays a crucial role in DNA replication, repair, and recombination as well as replication fork restarts. SSB is essential for cell survival and, thus, is an attractive target for potential antipathogen chemotherapy. Whether naturally occurring products can inhibit SSB remains unknown. In this study, the effect of the flavonols myricetin, quercetin, kaempferol, and galangin on the inhibition of Pseudomonas aeruginosa SSB (PaSSB) was investigated. Furthermore, SSB was identified as a novel quercetin-binding protein. Through an electrophoretic mobility shift analysis, myricetin could inhibit the ssDNA binding activity of PaSSB with an IC50 of 2.8 ± 0.4 μM. The effect of quercetin, kaempferol, and galangin was insignificant. To elucidate the flavonol inhibition specificity, the crystal structure of PaSSB complexed with the non-inhibitor quercetin was solved using the molecular replacement method at a resolution of 2.3 Å (PDB entry 7VUM) and compared with a structure with the inhibitor myricetin (PDB entry 5YUN). Although myricetin and quercetin bound PaSSB at a similar site, their binding poses were different. Compared with myricetin, the aromatic ring of quercetin shifted by a distance of 4.9 Å and an angle of 31° for hydrogen bonding to the side chain of Asn108 in PaSSB. In addition, myricetin occupied and interacted with the ssDNA binding sites Lys7 and Glu80 in PaSSB whereas quercetin did not. This result might explain why myricetin could, but quercetin could not, strongly inhibit PaSSB. This molecular evidence reveals the flavonol inhibition specificity and also extends the interactomes of the natural anticancer products myricetin and quercetin to include the OB-fold protein SSB.

Studies towards the Total Synthesis of (+)-Discodermolide: Desymmetrization Approach

A new synthetic strategy for the construction of C-1 to C-7 and C-8 to C-15 subunits of (+)-discodermolide, a highly potent anticancer natural product, is reported in which we have exploited desymmetrization approach to create six stereogenic centers at once and stigmatic elements of the successful methodology include elaboration of two advanced fragments from a common precursor

Pd-Catalyzed Umpolung Chemistry of Glycal Acetates and Their [2,3]-Dehydrosugar Isomers.

Glycals and their [2,3]-dehydrosugar derivatives have commonly been used in synthetic chemistry as electrophiles. Here we report a Pd-catalyzed polar inversion (umpolung) of this reaction, where the glycals and isomers can be used as nucleophiles. The reaction showed high regio- and stereoselectivity in the presence of numerous aromatic and aliphatic aldehydes. The synthetic utility of this reaction was demonstrated by the short synthesis of the tetrahydropyran fragment of the anticancer natural product mucocin.

43 Natural Anticancer Products: Classified under the Cancer Hallmarks and the Available Evidence of their Anticancer Activities

About 60% of chemotherapeutic agents used for the treatment of cancer diseases today have been derived from natural products. While some of these agents are identical to the natural molecules found in plants; the others are semisynthetic derivative of the foundational molecule found naturally in the raw sources. Cancers have been reported to express 10 specific hallmark which are used as the key points or steps for targeted therapy against these cancers. Extending the number of these hallmarks to 12 this review article throws light on 43 natural products classifying them according to their target of action. Further, the natural products under consideration are categorized according to the level of evidence present for their anticancer activities.

Access to γ-Carbolines: Synthesis of Isocryptolepine.

A new method to synthesize γ-carboline derivatives has been developed starting from 3,5-dibromo-4-pyridinamine by monoarylation using the Suzuki-Miyaura cross-coupling reaction followed by the base-mediated ring closure to pyrrole formation. Synthesis of a series of γ-carboline derivations from the 4-brominated γ-carboline 4a has been achieved by employing various coupling reactions and N-alkylations. This method has been applied for the synthesis of the antimalarial and anticancer natural product isocryptolepine. The photophysical properties of novel γ-carboline derivations are also reported.

GSH/ROS Dual-Responsive Supramolecular Nanoparticles Based on Pillar[6]arene and Betulinic Acid Prodrug for Chemo-Chemodynamic Combination Therapy.

Chemodynamic therapy (CDT) based on intracellular Fenton reactions is attracting increasing interest in cancer treatment. A simple and novel method to regulate the tumor microenvironment for improved CDT with satisfactory effectiveness is urgently needed. Therefore, glutathione (GSH)/ROS (reactive oxygen species) dual-responsive supramolecular nanoparticles (GOx@BNPs) for chemo–chemodynamic combination therapy were constructed via host–guest complexation between water-soluble pillar[6]arene and the ferrocene-modified natural anticancer product betulinic acid (BA) prodrug, followed by encapsulation of glucose oxidase (GOx) in the nanoparticles. The novel supramolecular nanoparticles could be activated by the overexpressed GSH and ROS in the tumor microenvironment (TME), not only accelerating the dissociation of nanoparticles—and, thus, improving the BA recovery and release capability in tumors—but also showing the high-efficiency conversion of glucose into hydroxyl radicals (·OH) in succession through intracellular Fenton reactions. Investigation of antitumor activity and mechanisms revealed that the dramatic suppression of cancer cell growth induced by GOx@BNPs was derived from the elevation of ROS, decrease in ATP and mitochondrial transmembrane potential (MTP) and, finally, cell apoptosis. This work presents a novel method for the regulation of the tumor microenvironment for improved CDT, and the preparation of novel GSH/ROS dual-responsive supramolecular nanoparticles, which could exert significant cytotoxicity against cancer cells through the synergistic interaction of chemodynamic therapy, starvation therapy, and chemotherapy (CDT/ST/CT).

Gene Cluster Analysis of Marine Bacteria Seeking for Natural Anticancer Products

Background: In the past decade, metabolites of marine microorganisms have been increasingly used for their various biological activities. An intense effort has been dedicated to assessing the therapeutic efficacy of the marine natural products and metabolites obtained from marine bacteria in cancer therapy. Fast and reliable analytical bacterial genome sequencing provides specialized bioinformatic tools to identify potential gene clusters in bacteria for obtaining secondary metabolites. Objectives: This study aimed to analyze the genome sequences of marine bacteria to recognize bioactive compounds with anti-cancer properties. Methods: Marine bacteria with the genomic sequences registered in the National Center for Biotechnology Information (NCBI) genome database were used in this study. The genome was analyzed for proteins, tRNAs, and rRNAs from GenBank entries by Feature Extract 1.2L Server. The Anti-SMASH webserver was used for the analysis of unique marine bacterial metabolites of the marine bacterial genome, available from the NCBI database. Results: A number of marine bacterial species, including Salinispora arenicola, Salinispora tropica, Crocosphaera watsonii, and Blastopirellula marina encoded metabolites belonging to the polyketide and nonribosomal peptide (NRP) families, showing anti-cancer properties. Among the marine species described, S. tropica and S. arenicola are richer in the genes encoding polyketide and NRP with potential antitumor activities. Conclusions: Marine bacteria are an excellent and exceptional source of anti-cancer compounds. In silico genome analysis of marine bacteria provided an opportunity to evaluate gene clusters for known natural products. Like this chemical engineering approaches for pharmaceutical application are useful in clinical evaluation of cancer treatment.

ACNPD: The Database for Elucidating the Relationships Between Natural Products, Compounds, Molecular Mechanisms, and Cancer Types.

Objectives: Cancer is well-known as a collection of diseases of uncontrolled proliferation of cells caused by mutated genes which are generated by external or internal factors. As the mechanisms of cancer have been constantly revealed, including cell cycle, proliferation, apoptosis and so on, a series of new emerging anti-cancer drugs acting on each stage have also been developed. It is worth noting that natural products are one of the important sources for the development of anti-cancer drugs. To the best of our knowledge, there is not any database summarizing the relationships between natural products, compounds, molecular mechanisms, and cancer types.Materials and methods: Based upon published literatures and other sources, we have constructed an anti-cancer natural product database (ACNPD) (http://www.acnpd-fu.com/). The database currently contains 521 compounds, which specifically refer to natural compounds derived from traditional Chinese medicine plants (derivatives are not considered herein). And, it includes 1,593 molecular mechanisms/signaling pathways, covering 10 common cancer types, such as breast cancer, lung cancer and cervical cancer.Results: Integrating existing data sources, we have obtained a large amount of information on natural anti-cancer products, including herbal sources, regulatory targets and signaling pathways. ACNPD is a valuable online resource that illustrates the complex pharmacological relationship between natural products and human cancers.Conclusion: In summary, ACNPD is crucial for better understanding of the relationships between traditional Chinese medicine (TCM) and cancer, which is not only conducive to expand the influence of TCM, but help to find more new anti-cancer drugs in the future.

Asymmetric Total Synthesis of Amphirionin-2.

A convergent route for the asymmetric total synthesis of potent anticancer polyketide natural product amphirionin-2 has been developed. Our initial synthetic trials revealed that the proposed structures of amphirionin-2 need to be revised consistent with a recent report of Fuwa et al., where the actual structure of amphirionin-2 was established. The key features of our synthesis comprised Sharpless asymmetric dihydroxylation, followed by cycloetherification, Wittig olefination, Julia-Kocienski olefination, and Crimmins propionate aldol reaction.

Two Worlds Colliding: The Interplay Between Natural Compounds and Non-Coding Transcripts in Cancer Therapy.

Cancer is a devastating disease and has recently become the leading cause of death in western countries, representing an immense public health burden. When it comes to cancer treatment, chemotherapy is one of the main pillars, especially for advanced stage tumors. Over the years, natural compounds have emerged as one of the most valuable resources for new chemotherapies. It is estimated that more than half of the currently used chemotherapeutic agents are derived from natural compounds. Usually, natural compounds are discovered empirically and an important limitation of introducing new anti-cancer natural products is lack of knowledge with regard to their mechanism of action. Recent data has proven that several natural compounds may function via modulating the expression and function of non-coding RNAs (ncRNAs). NcRNAs are a heterogenous class of RNA molecules which are usually not translated into proteins but have an important role in gene expression regulation and are involved in multiple tumorigenic processes, including response/resistance to pharmacotherapy. In this review, we will discuss how natural compounds function via ncRNAs while summarizing the available data regarding their effects on over 15 types of cancer. Moreover, we will critically analyze the current advances and limitations in understanding the way natural compounds exert these health-promoting effects by acting on ncRNAs. Finally, we will propose several hypotheses that may open new avenues and perspectives regarding the interaction between natural compounds and ncRNAs, which could lead to improved natural compound-based therapeutic strategies in cancer.

A Promising Anticancer Agent Dimethoxycurcumin: Aspects of Pharmacokinetics, Efficacy, Mechanism, and Nanoformulation for Drug Delivery.

Curcumin is a well-known anticancer natural product with various significant bioactivities that has been well documented, but its widespread use is mainly hindered by insufficient ADME properties such as poor solubility and low metabolic stability. Dimethoxycurcumin (DiMC) is a kind of lipophilic compound derived from curcumin that maintains its anticancer potency and has greatly improved systematic bioavailability. Therefore, DiMC is regarded as a promising plant-derived anticancer agent that deserves to be well developed. Herein, we concentrate on the published work by those from original research groups concerned with the pharmacokinetics, efficacy, and mechanism of DiMC involved in the treatment of various tumors, as well as the nanoformulations for effective drug delivery.

Walsura robusta Roxb. (Meliaceae), a little-known tree with a rich limonoid profile

The plant Walsura robusta Roxb. (Meliaceae) is a robust tree largely distributed in south-east Asia, including provinces of southern China. A few traditional usages of the plant have been mentioned, notably for the treatment of microbial infections. But experimental studies using different types of plant extracts only revealed modest antibacterial effects, and no major antiparasitic activity. Walsura robusta Roxb. is a rich source of secondary metabolites. Several series of limonoids have been isolated from the leaves or the fruits of the plant, such as walsuronoid A-I, walsurins A-E, walsunoids A-I, walrobsins A-R and other cedrelone- or dihydrocedrelone-type limonoids, in addition to a few other terpenoids. All information about Walsura robusta Roxb. have been collated in this brief review. The analysis underlines the presence of two limonoids endowed with significant anticancer activities, walsuronoid B and cedrelone. They both activate the production of reactive oxygen species in cancer cells, modulate mitochondrial activities and induce apoptosis of cancer cells. Their molecular targets and mechanism of action are discussed. Walsura robusta Roxb. has a potential for the development of anticancer natural products. The use of the plant extracts could be further considered for the treatment of diseases with a cell proliferation component.

Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil.

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

Anticancer natural products from Aspergillus neoniger, an endophyte of Ficus carica

BackgroundSeveral plants have not been investigated for their endophytes, such as the medicinal plant Ficus carica for which anticancer activity has been confirmed. The endophyte Aspergillus neoniger was selected for investigation of its metabolites since it exerted anticancer activities in preliminary screening assays.ResultsBioactivity-guided chromatographic fractionation was performed on the endophytic extract and resulted in the identification of asperazine and asperazine A through spectroscopic analysis. Moderate cytotoxicity against HeLa cell lines (CC50 = 18.4 µg mL−1) and moderate antiproliferative effects against HUVEC and K-562 cell lines (GI50 = 31.5 and 24.8 µg mL−1, respectively) were observed for asperazine. Asperazine A on the other hand showed weak cytotoxic activity against HeLa cell lines (CC50 = 34.6 µg mL−1) as well as weak cytostatic activities against HUVEC and K-562 cell lines (GI50 = 40.7 and 50.2 µg mL−1, respectively) while no antimicrobial activity was detected for both compounds.ConclusionsThese results suggest contribution of A. neoniger to the reported anticancer activity of the host plant and provides a new source of anticancer metabolites with therapeutic potential.

Defining a Role of Amanita phalloides Toxins in Cancer: Research and Therapy

Despite the progress of diagnostic and therapy, the cancer burden is still rising worldwide. The new chemotherapeutical toxicity to somatic cells and its tolerance to tumor cells illustrates the immediate demand through recent pharmaceutical products with less harmful impacts. The use of natural anticancer products, like alpha-amanitin toxins have reached the cancer field therapy since the separation of Amanita phalloides fungi was performed. Application of Amanita phalloides affects tumor cell activity. It is thought that Amanita phalloides dilutions are recommended for a patient suffering from various cancer types and have no severe side effects resulting from amanita therapy. This review aims to explain the use of the therapeutic potential of -amanitin toxin against different cancer types.

Exosome-Based Delivery of Natural Products in Cancer Therapy.

A rapidly growing research evidence has begun to shed light on the potential application of exosome, which modulates intercellular communications. As donor cell released vesicles, exosomes could play roles as a regulator of cellular behaviors in up-taken cells, as well as a delivery carrier of drugs for targeted cells. Natural product is an invaluable drug resources and it is used widely as therapeutic agents in cancers. This review summarizes the most recent advances in exosomes as natural product delivery carriers in cancer therapy from the following aspects: composition of exosomes, biogenesis of exosomes, and its functions in cancers. The main focus is the advantages and applications of exosomes for drug delivery in cancer therapy. This review also summarizes the isolation and application of exosomes as delivery carriers of natural products in cancer therapy. The recent progress and challenges of using exosomes as drug delivery vehicles for five representative anti-cancer natural products including paclitaxel, curcumin, doxorubicin, celastrol, and β-Elemene. Based on the discussion on the current knowledge about exosomes as delivery vehicles for drugs and natural compounds to the targeted site, this review delineates the landscape of the recent research, challenges, trends and prospects in exosomes as delivery vehicles for drugs and natural compounds for cancer treatment.