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Cytotoxic Activity and Molecular Docking Studies of the Fraction Containing Ergosta-14,22-dien-3-ol (3β, 5α, and 22E) from Dysidea avara Sponges
Abstract
Background: Cancer is a global health burden, and the discovery of novel therapeutic agents remains a critical pursuit. Marine organisms, including sponges, have emerged as a promising source of structurally diverse natural products with potential anticancer properties. Objectives: In the present study, the cytotoxic activity of the fraction containing Ergosta-14,22-dien-3-ol (3β, 5α, and 22E), a steroid compound derived from Dysidea avara, was evaluated against Jurkat/E6-1 and Hek293 cells. Methods: Multiple analytical techniques, including column chromatography, TLC, and GC-MS, were used to isolate and identify the compound from marine sponges from the Persian Gulf. The XTT assay determined the cytotoxic activity and western blot for P53 expression in the Jurkat/ E6-1 cell line. The compound was also docked within the poly (ADP-ribose) polymerase-1 (PARP1) and E3 ubiquitin-protein ligase (MDM2) to investigate its potential mechanism of action. Furthermore, the pharmacological properties of the compound were predicted using PerADME, SwissADME, and Molinspiration tools. Results: The results showed that Ergosta-14,22-dien-3-ol (3β, 5α, and 22E) exhibited significant cytotoxic activity against Jurkat/E6-1 cells with an IC50 of 26.59 μg/mL. Western blotting analysis demonstrated a noticeable increase in the expression of P53 protein in cells treated with 50 and 100 µg/mL of the compound. In silico analysis revealed adequate binding energy against PARP1 and E3 MDM2 receptors. The compound also demonstrated favorable pharmacokinetic characteristics, specifically in absorption, distribution, metabolism, and excretion (ADME). Conclusions: Ergosta-14,22-dien-3-ol (3β, 5α, and 22E) has the potential to be developed as a promising anti-cancer agent.
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Ubiquitination is one of the most important post-translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.
Background
Sea cucumber is a natural resource-rich in many important pharmacological compounds. this study aimed to investigate the effect of H. leucospilota extract on the induction of cell death and Proapoptotic Activities.
Methods and Results
H. leucospilota was collected, the methanolic extract was prepared and in vitro cytotoxicity of H. leucospilota extract in the range of 12.5, 25, 50, 100, and 200 μg/mL concentrations for 48 hours on SK-BR-3 and MCR5 cells was determined. Analysis of apoptosis and cell cycle stages were performed using flow cytometry. the expressions of several apoptotic-related proteins in SK-BR-3 cells were evaluated using Western blot analysis. ROS formation and caspase activity were determined. GC-MS (involving a multistep temperature gradient and trimethylsilyl derivatives) and phytochemical analysis were used for the identification of bioactive compounds. The methanolic extract inhibited the proliferation of the SK-BR-3 cell line in a dose- and time-dependent manner. As it was observed, exposure of the H. leucospilota extract triggered the apoptosis of the SK-BR-3 cells, induced DNA fragmentation, and arrested the cells in the G2/M phase. treatment of the methanolic extract induced the downregulation of antiapoptotic Bcl-2 protein as well as the upregulation of Bax, caspase-3, caspase-7 proteins in SK-BR-3 cells. Methanolic extract-elicited apoptosis was accompanied by an elevated level of ROS. The GC-MS and phytochemical analysis revealed 30 compounds and the extract contained alkaloids, flavonoids, steroids, terpenoids, phenols, and saponins.
Conclusions
The antiproliferative and proapoptotic activities of the tested extract suggested the pharmacologic potential of H. leucospilota. Correspondingly, further characterizations of the identified compounds are in progress.
Natural products, with remarkable chemical diversity, have been extensively investigated for their anticancer potential for more than a half-century. The collective efforts of the community have achieved the tremendous advancements, bringing natural products to clinical use and discovering new therapeutic opportunities, yet the challenges remain ahead. With remarkable changes in the landscape of cancer therapy and growing role of cutting-edge technologies, we may have come to a crossroads to revisit the strategies to understand nature products and to explore their therapeutic utility. This review summarizes the key advancements in nature product-centered cancer research and calls for the implementation of systematic approaches, new pharmacological models, and exploration of emerging directions to revitalize natural products search in cancer therapy.
Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysi-dea avara compared with betamethasone-treated mice in in-vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.
Background:
Marine sponge is a rich natural resource of many pharmacological compounds and various bioactive anticancer agents are derived from marine organisms like sponges.
Methods:
studying the anticancer activity and Drug ability of marine sponge Dysidea avara using Cell lines oral epithelial cancer cell (KB/C152) and T-lymphocytic leukemia cell line (Jurkat/ E6-1). Marine sponge was collected from Persian Gulf. Several analytical techniques have been used to obtain and recognize stigmasterol, including column chromatography, thin layer chromatography, and gas chromatography-mass spectrometry. The PASS Prediction Activity was used to investigate the apoptosis-inducing effect of stigmasterol. The cytotoxic activity of stigmasterol was examined using yellow tetrazolium salt XTT (sodium 2, 3,-bis (2methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium) assay. The stigmasterol were docked within the protein tyrosine kinase (PTKs) (PDB code: 1t46) and epidermal growth factor receptor (EGFRK) (PDB code: 1M17). Also, the pharmacological characteristics of stigmasterol were predicted using PerADME, SwissADME, and Molinspi ration tools. Apoptosis-inducing effect of stigmasterol indicate the stigmasterol in terms of the possibility of apoptosis in cells.
Results:
The apoptosis inducement results of known stigmasterol were determined by PASS on-line prediction. The compound exhibit potent cytotoxic properties against KB/C152 cell compared to Jurkat/ E6-1 cell. The stigmasterol showed the cytotoxicity effects on KB/C152 and HUT78 with IC50 ranges of 81.18 and 103.03 μg/ml, respectively. Molecular docking showed that, stigmasterol bound stably to the active sites of the protein tyrosine kinase (PTKs) (PDB code: 1t46) and epidermal growth factor receptor (EGFRK) (PDB code: 1M17).
Conclusion:
The compound showed desirable pharmacokinetic properties (ADME). This provided direct evidence of how a prospective anti-cancer agent can be stigmasterol. The preclinical studies paved the way for a potential new compound of anti-cancer.
Cancer represents one of the leading causes of death worldwide. Progresses in treatment of cancer have continued at a rapid pace. However, undesirable side effects and drug resistance remain major challenges for therapeutic success. Natural products represent a valuable starting point to develop new anticancer strategies. Polyphenols, well-known as antioxidant, exert anticancer effects through the modulation of multiple pathways and mechanisms. Oat (Avena sativa L., Poaceae) is a unique source of avenanthramides (AVAs), a group of polyphenolic alkaloids, considered as its signature compounds. The present review aims to offer a comprehensive and critical perspective on the chemopreventive and chemotherapeutic potential of AVAs. AVAs prevent cancer mainly by blocking reactive species. Moreover, they exhibit potential therapeutic activity through the modulation of different pathways including the activation of apoptosis and senescence, the block of cell proliferation, and the inhibition of epithelial mesenchymal transition and metastatization. AVAs are promising chemopreventive and anticancer phytochemicals, which need further clinical trials and toxicological studies to define their efficacy in preventing and reducing the burden of cancer diseases.
Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.
The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway. MDM2 amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53-MDM2 loop-dependent and p53-MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by MDM2 amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.
Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53.Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression. Murine double minute 2 (MDM2) is the negative regulator of p53 gene forming an autoregulatory feedback loop controlling each other cellular levels. Murine double minute 2 is unique E3 ubiquitin ligase protein which is responsible for ubiquitination and degradation of p53 gene. Many drugs/compounds have been developed for reactivation of p53 gene by inhibiting MDM2 interaction with p53, using MDM2 antagonism, inhibiting E3 ubiquitination of p53. Many compounds have entered clinical trials in haematological malignancies. This review will throw some light on reactivation of p53 gene by MDM2 and its homologues.
Poly(ADP-ribose) polymerase-1 (PARP1) is key protein involved in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly, or via PARylation with various oncogenic proteins and regulates several transcription factors, thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy, and a number of PARP inhibitors (PARPi) are in different stages of clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics. The potential of PARPi as chemopotentiator, radiosensitizer, or adjuvant therapeutic agents has been established in several clinical studies. Recent studies have shown that PARP1 could be either tumor suppressive or oncogeneic in different cancers. PARPi resistance is also a growing concern in the clinical setting. Recently, changes in the levels of PARP1 activity or expression in cancer patients has provided a basis for consideration of PARP1 regulatory proteins as potential biomarkers. This review focuses on the current developments related to the role of PARP in cancer progression, therapeutic strategies targeting PARP-associated oncogenic signaling, and future opportunities in the use of PARPi in anticancer therapeutics.
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Objectives:
Marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the Arabian Gulf and the Gulf of Oman. This study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the Gulf of Oman.
Methods:
This study was carried out between January 2012 and December 2014 at the Sultan Qaboos University, Muscat, Oman. Fungi, bacteria, sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers were collected from seawater at Marina Bandar Al-Rowdha and Bandar Al-Khayran in Oman. Bacteria and fungi were isolated using a marine broth and organisms were extracted with methanol and ethyl acetate. Compounds were identified from spectroscopic data. The anti-cancer activity of the compounds and extracts was tested in a Michigan Cancer Foundation (MCF)-7 cell line breast adenocarcinoma model.
Results:
Eight pure compounds and 32 extracts were investigated. Of these, 22.5% showed strong or medium anti-cancer activity, with malformin A, kuanoniamine D, hymenialdisine and gallic acid showing the greatest activity, as well as the soft coral Sarcophyton sp. extract. Treatment of MCF-7 cells at different concentrations of Sarcophyton sp. extracts indicated the induction of concentration-dependent cell death. Ultrastructural analysis highlighted the presence of nuclear fragmentation, membrane protrusion, blebbing and chromatic segregation at the nuclear membrane, which are typical characteristics of cell death by apoptosis induction.
Conclusion:
Some Omani marine organisms showed high anti-cancer potential. The efficacy, specificity and molecular mechanisms of anti-cancer compounds from Omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies.
Why write a book on sponge taxonomy; who would read such a book; what is the relevance of sponges; and what are sponges anyway?
Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.
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Background
The marine environment having vast resources of natural products with potential bioactivities. Among the marine natural products, fatty acids obtained from marine mollusks have broad range of biological activities including antimicrobial and antitumor activities. The present study aims to characterize the fatty acid derivatives from the Sydney rock oyster Saccostrea glomerata and its pharmacological activities.
Methods
S. glomerata fleshes were serially extracted with hexane, ethyl acetate and methanol and studied the antimicrobial activities against pathogenic bacteria, fungi and virus. Based on the better result, the ethyl acetate extract was selected and purified through silica column chromatography and screened the fractions for antimicrobial and antitumor activities. Also the best active fraction (FV) was functionally and structurally characterized.
Results
The ethyl acetate extract of S. glomerata effectively controlled the bacterial pathogens and formed of more than 15 mm of zone of inhibition and also effectively suppressed the fungal growth and inhibit the shrimp white spot syndrome virus (WSSV). The secondary screening results revealed that, the fraction (FV) had potential antimicrobial and antitumor activities. The FV concentration (100 μg/ml) effectively suppressed the tumor mammary epithelial carcinoma cell of 14.45%. The GC–MS analysis revealed that, eleven compounds including N-hexadecanoic acid, L-(+)-ascorbic acid 2,6-dihexadecanoate and 6-Octadecenoic acid were characterized.
Conclusions
The fatty acid derivatives isolated and characterized from S. glomerata extracts had the potent antimicrobial and antitumor activities. This basic research can help to develop the antimicrobial and anticancer drugs from the nutraceuticals in future.
Drug development using marine bioresources is limited even though the ocean occupies about 70% of the earth and contains a large number of biological materials. From the screening test of the marine sponge extracts, we found Hyrtios sp. sponge collected from Chuuk island, Micronesia. In this study, the Hyrtios sp. extract was examined for anticancer activity against human colorectal carcinoma RKO cells that are wildtype for p53 and RKO-E6 that are p53 defective. The Hyrtios sp. extract dose-dependently inhibited viability in both cell lines. Multinucleation as an indication of mitotic catastrophe was also observed. Cytotoxicity tests gave significantly different results for RKO and RKO-E6 cells after 48 h exposure to Hyrtios sp. extract. In RKO cells treated with Hyrtios sp. extract, cell death occurred by induction of p53 and p21 proteins. In p53-defective RKO-E6 cells, Hyrtios sp. extract decreased expression of JNK protein and increased p21 protein. These results indicate that Hyrtios sp. extract induced apoptosis via different pathways depending on p53 status and could be a good natural product for developing new anticancer drugs.
Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.
This study identified flavonoid glycosides in species of the genus Alchemilla, A. procerrima, A. stricta, A. hirtipedicellata and A. sericata. A. procerrima is an endemic species for Turkey. After detailed investigation, flavonoid compounds of the species were identified for the first time. In this study, flavonoid compounds were determined by using two different chromatography techniques, TLC and HPLC. The following flavonoid compounds were identified from the Alchemilla species studied. They are as follows: orientin (luteolin-8-C-glucoside) Rf: 0,70, vitexin (apigenin-8-C-glucoside) Rf: 0,77 as flavone-C-glycoside, rutin (quercetin-3-O-rutinoside) Rf: 0,44, hyperoside (quercetin-3-O-galactoside) Rf: 0,65, isoquercetin (quercetin-3-O-glucopyranoside) Rf: 0,72, quercitrin (quercetin-3-O-rhamnoside) Rf: 0,84 as flavonol-O-glycoside. Three more folavonoids with Rf values of Rf1 = 0,36, Rf2 =0,54 and Rf3 =0,68 were also identified for the first time in this study. Rutin (quercetin-3-O-rutinoside) and the flavonoid glycoside, shown as Rf2 were found in all species. Quercitrin and isoquercetin were determined in all analysed species but A. procerrima. Hyperoside was identified in all species except for A. stricta. Vitexin was determined only in A.stricta. Orientin was determined in A. procerrima and A. stricta, but could not be determined in A. sericata and A. hirtpedicellata. Unknown flavonoid with Rf 1 and Rf 3 were determined outside of A. sericata. Description of these compounds in Turkish Alchemilla plants for the first time should be viewed as a discovery of an important chemosystematic feature.
The ethanol extract of an Indonesian marine sponge Lamellodysidea
herbacea inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), an important target enzyme for the treatment of type II diabetes. Bioassay-guided isolation yielded a known polybromodiphenyl ether (1) as a sole bioactive component. The structure of 1 was confirmed by spectroscopic data for 1 and its methyl ether derivative (2). Compound 1 markedly inhibited the PTP1B activity (IC50 = 0.85 μM) and showed a moderate cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells. On the other hand, compound 2 maintained potent inhibitory activity against PTP1B (IC50 = 1.7 μM) but did not show apparent cytotoxicity at 18 μM against these cancer cells. Four ester derivatives [acetyl (3), butyryl (4), hexanoyl (5), and benzoyl (6)] were prepared from 1 and their activities evaluated against PTP1B and two cancer cell lines to investigate the structure–activity relationships. Although compounds 3–6 exhibited potent inhibitory effects against PTP1B activity, cytotoxicity against HCT-15 and Jurkat cells was observed as a similar efficacy to that of 1. From these results, compound 2 was found to be the best inhibitor of PTP1B with no apparent cytotoxicity. Therefore, 2 may be a lead compound for making a new type of PTP1B inhibitor. Moreover, compound 2 did not inhibit the cell growth of Huh-7 cells (hepatoma). Hepatocytes are one of the locations of PTP1B, and Huh-7 cells are used to study the mechanism of action of compound 2.
Marine ecosystems constitute a huge reservoir of biologically active secondary metabolites. Consequently during the last past few decades, several marine-derived molecules have been approved for anticancer treatment or are under clinical trials. This review reports the present state of the art of the sixteen molecules approved or currently on the clinical pipeline for anticancer chemotherapy. The molecules are classified according to their current status in the phase (approved / phase IV / phase III / phase II / phase I) and data are updated to April 2012.
represent landmarks in the history of medicine. Almost 60% of drugs approved for cancer treatment are of natural origin. Vincristine, irinotecan, etoposide, taxanes and camptothecines are all examples of plant-derived compounds. Dactinomicine, anthracyclines, mitomycin and bleomycin are anticancer agents derived from microbial sources (1). Although marine compounds are under-represented in current pharmacopoeia, it is anticipated that the aquatic environment will become an invaluable source of novel compounds in the future. The marine ecosystem represents 95% of the biosphere, and all except one of the 33 animal phyla are represented in aquatic environ- ments (2). Most sessile marine invertebrates contain a primitive immune system and produce toxic chemicals as a form of defense. Many of these products act as regulators of specific biological functions. Some of them have pharmacological activity due to their specific interactions with receptors and enzymes. Because these substances become immediately diluted by large volumes of seawater, they need to be highly potent on a molar basis, and also have to retain a relatively low solubility (3). The development of marine compounds as therapeutic agents is still in its infancy due to the lack of an analogous ethno-medical history as compared with terrestrial habitats, together with the relative technical difficulties in collecting marine organisms. Over the last few decades significant efforts have been made, by both pharmaceutical companies and academic institutions, to isolate and identify new marine-derived, natural products. These initiatives have been accompanied by funding support from govern- mental agencies. Specific programs directed towards the collection and characterization of marine natural products and evaluation of their biological activity have been established (4). This systematic investigation of marine environments is reflected in the large number of novel compounds reported in the literature over the past decade (5). Some of these agents have entered preclinical and clinical trials, and it may be expected that this number will increase in the future. This article will review some of the tech- nical strategies that are being employed to collect and identify novel marine products with potential antitumoral properties, and will also provide a summary of the available clinical trial informa- tion of agents with promising activity.
The analysis of cell signaling requires the rapid and selective manipulation of protein function. We have synthesized photoswitches that covalently modify target proteins and reversibly present and withdraw a ligand from its binding site due to photoisomerization of an azobenzene linker. We describe here the properties of a glutamate photoswitch that controls an ion channel in cells. Affinity labeling and geometric constraints ensure that the photoswitch controls only the targeted channel, and enables spatial patterns of light to favor labeling in one location over another. Photoswitching to the activating state places a tethered glutamate at a high (millimolar) effective local concentration near the binding site. The fraction of active channels can be set in an analog manner by altering the photostationary state with different wavelengths. The bistable photoswitch can be turned on with millisecond-long pulses at one wavelength, remain on in the dark for minutes, and turned off with millisecond long pulses at the other wavelength, yielding sustained activation with minimal irradiation. The system provides rapid, reversible remote control of protein function that is selective without orthogonal chemistry.
• azobenzene
• ion channel
• photoisomerization
• optical switch
• remote control
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL.
E3 ubiquitin ligases are a large family of proteins that are engaged in the regulation of the turnover and activity of many target proteins. Together with ubiquitin-activating enzyme E1 and ubiquitin-conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a variety of biologically significant protein substrates for targeted degradation through the 26S proteasome, as well as for nonproteolytic regulation of their functions or subcellular localizations. E3 ubiquitin ligases, therefore, play an essential role in the regulation of many biologic processes. Increasing amounts of evidence strongly suggest that the abnormal regulation of some E3 ligases is involved in cancer development. Furthermore, some E3 ubiquitin ligases are frequently overexpressed in human cancers, which correlates well with increased chemoresistance and poor clinic prognosis. In this review, E3 ubiquitin ligases (such as murine double minute 2, inhibitor of apoptosis protein, and Skp1-Cullin-F-box protein) will be evaluated as potential cancer drug targets and prognostic biomarkers. Extensive study in this field would lead to a better understanding of the molecular mechanism by which E3 ligases regulate cellular processes and of how their deregulations contribute to carcinogenesis. This would eventually lead to the development of a novel class of anticancer drugs targeting specific E3 ubiquitin ligases, as well as the development of sensitive biomarkers for cancer treatment, diagnosis, and prognosis.
A C16 norsesterterpenoid (euplectellodiol, 1) and a norditerpenoid (2) have been isolated from the marine sponges Mycale euplectelloides and Diacarnus megaspinorhabdosa, respectively. Their structures have been determined by spectroscopic methods. Compounds 1 and 2 are new natural products.
This study aims to investigate the chemical constituents of sponges Dysidea avara (D. avara) and Axinella sinoxea (A. sinoxea), grown up in the Persian Gulf, as well as dehydrodeoxycholic acid (DHCA) content in methanolic extracts of the selected sponges. The chromatography-mass spectrometry (GC-MS) fingerprint of bioactive compounds from methanolic extracts of the selected marine sponge samples was investigated. Based on molecular docking results, among chemical compounds found in marine sponges, DHCA has anti-inflammatory and antipsoriatic properties. They also indicated that DHCA generated stable complexes with 1w81, 3bqm, and 3k8o receptors (psoriasis-related targets) with a binding energy (BE) of -9.26, -10.62, and -7.59 kcal mol⁻¹, respectively. DHCA is isolated from the methanolic extracts of marine sponge samples on chromatographic plates was quantified after derivatization with anisaldehyde reagent by the validated HPTLC method. In-situ HPTLC-DPPH was also calculated to evaluate the free radical-scavenging activity (FRSA) of DHCA. In-silico ADME (Absorption, Distribution, Metabolism, Excretion) predictions revealed that the compound had minimum toxicity and acceptable human intestinal absorption (HIA), as well as low skin permeability. These can potentially be employed as lead compounds to develop a novel antipsoriatic drug.
Three known polybromobiphenyl ether derivatives, 2-(2′,4′-dibromophenoxy)-3,5-dibromophenol (1), 2-(2′,4′-
dibromophenoxy)-4,6-dibromophenol (2), and 2-(2′-dibromophenoxy)-3,4,5,6-tetrabromophenol (3), were
identified as PTP1B inhibitors from the Indonesian marine sponge Lamellodysidea sp. (cf.L. herbacea) together
with two new monocyclofarnesol-derived sesquiterpenes, lamellolactones A (4) and B (5). The structures of 4
and 5 were elucidated based on their spectroscopic data and comparisons with those for related compounds.
Compounds 1–3 inhibited PTP1B activity with IC 50 values of 5.3, 7.8, and 5.3 μM, respectively, while com-
pounds 4 and 5 were not active at 38–40μM. The selective activities of 1–3 against PTP1B over the other PTPs
(T-cell PTP, CD45 tyrosine phosphatase, and vaccinia H-1-related phosphatase) showed that the position and/or
number of Br atoms affected their inhibitory activities.
Depression is a critical mood disorder that affects millions of patients. Available therapeutic antidepressant agents are associated with several undesirable side effects. Recently, it has been shown that Neurokinin 1 receptor (NK1R) antagonists can potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs). In this study, a series of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and NK1R antagonism/SERT inhibitory of these compounds. The best multiple linear regression equation was obtained from GA-PLS and MLR for NK1R and SERT, respectively. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed for both targets. Molecular docking studies of these compounds on both targets were also conducted and encouraging results were acquired. There was a good correlation between QSAR and docking results. The results obtained from validated docking studies indicate that the important amino acids inside the active site of the cavity that are responsible for essential interactions are Glu33, Asp395 and Arg26 for SERT and Ala30, Lys7, Asp31, Phe5 and Tyr82 for NK1R receptors.
The biological properties of various metabolites from sponges reported recently and marine sponges are considered as a gold mine for past 50 years. Sponge-derived compounds and their metabolites have different types of biological activity such as antimicrobial, antiinflammatory, antimalarial, antioxidant, anti-HIV, and anticancer activity. Angiogenesis is the important process in tumor progression. The term “angiogenic switch” refers to a very important event during the tumor progression between pro- and antiangiogenic factors. Angiogenesis and its mechanistic pathway targeting may be useful for therapeutic approach for cancer. Recent times many compounds from marine sources have proven important role against cancer. These compounds inhibit cell proliferation and angiogenesis of cancer. In this chapter, we discuss the antiangiogenic compounds isolated from marine sponge that work against cancer.
In continuation of our efforts to identify bioactive compounds from the Red Sea marine sponges, we have recently investigated the organic extract of the sponge Biemna ehrenbergi. This study resulted in the isolation of eight compounds including a new sterol, ehrenasterol (1), a new C24-acetylenic acid, biemnic acid (2), together with six known compounds including a hopanoid, three steroids and two nucleosides. The isolated compounds were identified as (22E)-ergosta-22-ene-8,14-epoxy-3,7-dione (1), (E)-tetracos-8-en-5-ynoic acid (2), (22E)-ergosta-5,8,22-trien-7-one-3β-ol (3), 32,35-anhydrobacteriohopanetetrol (4), (24R)-ergosta-6,22-diene-5,8-epidioxy-3-ol (5), melithasterol B (6), thymidine (7) and 2′-deoxyuridine (8). The structures of the isolated compounds were assigned by different spectral data including 1D and 2D NMR (COSY, HSQC, and HMBC) and high-resolution mass spectrometry. Compound 1 displayed inhibition zone of 20 mm at 100 μg/disc against Escherichia coli in the disc diffusion assay. Similarly, compounds 2 and 4 displayed inhibition zones of 20 and 18 mm respectively against Candida albicans at the same concentration. Compounds 1–3 displayed weak cytotoxic activity against human colon adenocarcinoma (HCT-116) cancer cell line.
Drug development has a high attrition
rate, with poor pharmacokinetic
and safety properties a significant hurdle. Computational approaches
may help minimize these risks. We have developed a novel approach
(pkCSM) which uses graph-based signatures to develop predictive models
of central ADMET properties for drug development. pkCSM performs as
well or better than current methods. A freely accessible web server
(http://structure.bioc.cam.ac.uk/pkcsm), which retains
no information submitted to it, provides an integrated platform to
rapidly evaluate pharmacokinetic and toxicity properties.
Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant, ubiquitously expressed NAD+-dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP-1 activity serves to poly (ADP-ribose)-ylate the vast majority of known client proteins and affects a number of cellular and biological outcomes, by mediating DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP-1 is also critically important for the maintenance of genomic integrity, as well as chromatin dynamics and transcriptional regulation. Evidence also indicates that PARP-directed therapeutics are "synthetic lethal" in BRCA1/2-dieficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP-1, which has profound implications for human malignancies and will be reviewed herein.
Leading the way in imposing a policy of zero tolerance of cellular abnormalities that might lead to tumor development is the p53 protein. The efficiency of p53 in preventing cell growth is a strong deterrent to malignant progression, but this activity must be kept tightly restrained to allow normal cell growth and development. Essential components of this regulation are the mechanisms by which the p53 protein is degraded, and efficient turnover of p53 in normal cells prevents the accumulation of the protein. Modulation of these degradation pathways in response to stress leads to the rapid stabilization and accumulation of p53, and activation of the p53 response. It is now becoming clear that the Mdm2 protein is central to the regulation of p53 stability and multiple pathways exist through which the activity of Mdm2 can be inhibited. Defects in the ability to stabilize p53 are likely to contribute to malignant development, and restoration of this activity represents an extremely attractive possibility for tumor therapy.
Dysidavarones A-D (1-4), four new sesquiterpene quinones possessing the unprecedented "dysidavarane" carbon skeleton, were isolated from the South China Sea sponge Dysidea avara. The structures were established by spectroscopic methods, and the absolute configurations were determined using quantum mechanical calculation of the electronic circular dichroic (ECD) spectrum and exciton chirality CD method. Their cytotoxic activity against four human cancer cell lines and PTP1B inhibitory activity were also evaluated.
Since its discovery, the unique properties of the naturally occurring amino acid, L-ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine), have intrigued researchers for more than a century. This widely distributed thione is only known to be synthesized by non-yeast fungi, mycobacteria and cyanobacteria but accumulates in higher organisms at up to millimolar levels via an organic cation transporter (OCTN1). The physiological role of EGT has yet to be established. Numerous in vitro assays have demonstrated the antioxidant and cytoprotective capabilities of EGT against a wide range of cellular stressors, but an antioxidant role has yet to be fully verified in vivo. Nevertheless the accumulation, tissue distribution and scavenging properties, all highlight the potential for EGT to function as a physiological antioxidant. This article reviews our current state of knowledge. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
We describe a graphical system for automatically generating multiple 2D diagrams of ligand-protein interactions from 3D coordinates. The diagrams portray the hydrogen-bond interaction patterns and hydrophobic contacts between the ligand(s) and the main-chain or side-chain elements of the protein. The system is able to plot, in the same orientation, related sets of ligand-protein interactions. This facilitates popular research tasks, such as analyzing a series of small molecules binding to the same protein target, a single ligand binding to homologous proteins, or the completely general case where both protein and ligand change.
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
A new tetrazolium salt XTT, sodium 3'-[1-[(phenylamino)-carbonyl]-3,4-tetrazolium]-bis(4-methoxy-6- nitro)benzene-sulfonic acid hydrate, was evaluated for use in a colorimetric assay for cell viability and proliferation by normal activated T cells and several cytokine dependent cell lines. Cleavage of XTT by dehydrogenase enzymes of metabolically active cells yields a highly colored formazan product which is water soluble. This feature obviates the need for formazan crystal solubilization prior to absorbance measurements, as required when using other tetrazolium salts such as MTT. Bioreduction of XTT by all the murine cells examined was not particularly efficient, but could be potentiated by addition of electron coupling agents such as phenazine methosulfate (PMS) or menadione (MEN). Optimal concentrations of PMS or MEN were determined for the metabolism of XTT by the T cell lines HT-2 and 11.6, NFS-60 a myeloid leukemia, MC/9 a mast cell line and mitogen activated splenic T cells. When used in combination with PMS, each of these cells generated higher formazan absorbance values with XTT than were observed with MTT. Thus the use of XTT in colorimetric proliferation assays offer significant advantages over MTT, resulting from reduced assay time and sample handling, while offering equivalent sensitivity.
The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Many pharmaceutical agents have been discovered by screening natural products from plants, animals, marine organisms and microorganisms. Vincristine, irinotecan, etoposide and paclitaxel are examples of plant-derived compounds that are being employed in cancer treatment, and dactinomycin, bleomycin and doxorubicin are anticancer agents derived from microbial sources. Citarabine is an example of an anticancer agent originating from a marine source. Other agents originating from marine sources are bryostatin-1, aplidine, dolastatin 10 and ET-743, which have recently entered phase I and II clinical trials.
DMXAA is one of the first examples of a new class of anticancer agents that attack existing tumor blood vessels and thus deprives tumor tissue of an adequate blood supply. Its mechanism of action appears to rely on the induction within tumor tissue of cytokines, such as tumor necrosis factor. In experimental tumors, DMXAA interacts productively with radiation, hyperthermia and a number of chemotherapeutic drugs. This review discusses the mechanisms underlying such interactions and how these might be exploited in clinical cancer treatment.
The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a vascular disrupting agent that has demonstrated efficacy in combination with taxane-based chemotherapy in patients with advanced cancer. Complementary modes of action, a lack of pharmacokinetic interaction and distinct adverse effect profiles provide a strong rationale for combining these anticancer agents. In a Phase II trial in men with hormone refractory prostate cancer, DMXAA (ASA404) in combination with docetaxel achieved a prostate-specific antigen response in more patients than docetaxel therapy alone, and was generally well tolerated. Further clinical evaluation of this combination in this patient population is warranted.
Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear, zinc-finger, deoxyribonucleic acid (DNA)-binding protein that detects specifically DNA strand breaks generated by different genotoxic agents. Whereas activation of PARP-1 by mild genotoxic stimuli facilitates DNA repair and cell survival, severe DNA damage triggers different pathways of cell death, including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. Pharmacological inhibition or genetic ablation of PARP-1 results in a clear benefit in cancer treatment by different mechanisms, including selective killing of homologous recombinationdeficient tumor cells, downregulation of tumor-related gene expression, and decrease in the apoptotic threshold in the cotreatment with chemo- and radiotherapy. We summarize in this review the findings and concepts for the role of PARP-1 and poly(ADP-ribosylation) in the regulation of carcinogenesis and some of the preclinical and clinical data available for these agents, together with the challenges facing the clinical development of these agents.