Search

Four new copper(II) complexes were synthesized and characterized with the general formula [Cu(N–N)(Th)(NO3)], where N–N corresponds to the N-heterocyclic ligands 1,10-phenanthroline (phen), 2,2′-bipyridine (bipy), 4,7-diphenyl-1,10-phenanthroline (dpp), and 4,4-dimethyl-2,2′-bipyridine (dmbp) and Th represents the N,N-dibenzyl-N′-benzoylthiourea. Cytotoxic activities of the complexes against HCT116 (human colon carcinoma), HepG2 (human hepatocellular carcinoma), and non-tumor MRC-5 (human lung fibroblast) cells were investigated. The copper(II) complexes 1–4 were characterized by spectroscopic techniques while complexes 1 and 2 were studied using single-crystal X-ray diffraction as well. The complexes possessed a five-coordinated structure with one nitrate ligand as a monodentate at the axial position and two bidentate ligands N-heterocyclic and N,N-dibenzyl-N′-benzoylthiourea. The complexes showed promising IC50 values, ranging from 0.3 to 9.0 μM. Furthermore, interaction studies with biomolecules such as calf thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA), which can act as possible biological targets of the complexes, were carried out. The studies suggested that the compounds interact moderately with ct-DNA and BSA. Complexes 1, 2, and 4 did not lead to cell accumulation at any stage of the cell cycle but caused a significant increase in internucleosomal DNA fragmentation. Whereas, compound 3 caused cell cycle arrest in the S phase while doxorubicin caused cell cycle arrest in the G2/M phase. The effect of structural modifications on the metal compounds was correlated with their biological properties and it was concluded that an increase in biological activity occurred with increasing the extension of the diimine ligands. Thus, complex 3 was the most promising one. [ABSTRACT FROM AUTHOR]

Abstract: Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. [Copyright &y& Elsevier]

Abstract: Piplartine (piperlongumine, 5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. – Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials. [Copyright &y& Elsevier]

Abstract: (+)-Cordiaquinone J is a 1,4-naphthoquinone isolated from the roots of Cordia leucocephala that has antifungal and larvicidal effects. However, the cytotoxic effects of (+)-cordiaquinone J have never being explored. In the present study, the effect of (+)-cordiaquinone J on tumor cells viability was investigated, showing IC50 values in the range of 2.7–6.6μM in HL-60 and SF-295 cells, respectively. Studies performed in HL-60 leukemia cells indicated that (+)-cordiaquinone J (1.5 and 3.0μM) reduces cell viability and 5-bromo-2-deoxyuridine incorporation after 24h of incubation. (+)-Cordiaquinone J showed rapid induction of apoptosis, as indicated by phosphatidylserine externalization, caspase activation, DNA fragmentation, morphologic changes, and rapid induction of necrosis, as indicated by the loss of membrane integrity and morphologic changes. (+)-Cordiaquinone J altered the redox potential of cells by inducing the depletion of reduced GSH intracellular content, the generation of reactive oxygen species and the loss of mitochondrial membrane potential. However, pre-treatment of cells with N-acetyl-l-cysteine abolished most of the observed effects related to (+)-cordiaquinone J treatment, including those involving apoptosis and necrosis induction. [Copyright &y& Elsevier]

Abstract: Piplartine {5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propen-1-yl]-2(1H)-pyridinone} is an alkamide present in Piper species that exhibits promising anticancer properties. It was previously shown that piplartine is mutagenic in yeast and cultured mammalian cells. This study was performed to increase the knowledge on the mutagenic potential of piplartine using the Salmonella/microsome assay, V79 cell micronucleus and chromosome aberration assays, and mouse bone-marrow micronucleus tests. Piplartine was isolated from the roots of Piper tuberculatum. This extracted compound was unable to induce a mutagenic response in any Salmonella typhimurium strain either in the presence or absence of metabolic activation. Piplartine showed mutagenic effects in V79 cells, as there was an increased frequency of aberrant cells and micronuclei formation. In addition, piplartine administered at 50mg/kg did not induce micronucleus formation in vivo, but a dose of 100mg/kg induced an increase in the levels of micronucleus polychromatic erythrocytes (MNPCEs). Overall, these results provide further support that piplartine induces in vivo and in vitro mutagenicity in eukaryotic models. [Copyright &y& Elsevier]

Guatteria olivacea R.E. Fries is an Amazonian species known as 'envira-bobó' and 'envira-fofa' and is common in the states of Amazonas, Acre, and Pará. Recently, the essential oil from the leaves of this species has shown promising antitumor activity both in vitro and in vivo. The presence of isoquinoline-derived alkaloids, including aporphinoids and tetrahydroprotoberberine alkaloids, has also been previously reported. In our ongoing search for bioactive compounds from Annonaceae Amazonian plants, the bark of G. olivacea was investigated via classical chromatography techniques, which revealed nine compounds, eight isoquinoline-derived alkaloids, a rare alkaloid with a α-gem-dimethyltetradehydrocularine structure known as gouregine, seven known aporphinoid alkaloids: isopiline, O-methylisopiline, melosmine, 9-hydroxyiguattescine, dihydromelosmine, lysicamine, and guattouregidine, and one known pimaradiene diterpene: acanthoic acid. All the isolated compounds were described for the first time in the bark of G. olivacea, and their structures were elucidated by extensive analyses of their 1D and 2D NMR spectra in combination with MS data. The NMR data of the alkaloids isopiline, O-methylisopiline, melosmine, dihydromelosmine, and guattouregidine were revised due to incomplete data in the literature and some ambiguities. The in vitro cytotoxic activities of the isolated compounds were evaluated against human cancer (HepG2, KG-1a, and HCT116) and noncancerous (MRC-5) cell lines via the Alamar blue assay after 72 h of incubation. Among the compounds evaluated against human cancer cell lines, the most active was the oxoaporphine alkaloid lysicamine, which has strong activity against HCT116 cells, with an IC50 value of 6.64 µg/mL (22.79 µmol/L). Melosmine had a moderate effect on HCT116 cells, with an IC50 value of 16.77 µg/mL (49.70 µmol/L), whereas acanthoic acid had moderate effects on HepG2 and HCT116 cells, with IC50 values of 14.63 µg/mL (48.37 µmol/L) and 21.25 µg/mL (70.25 µmol/L), respectively. [ABSTRACT FROM AUTHOR]

In this review, we provide an overview of the current understanding of the main mechanisms of pharmacological action of essential oils and their components in various biological systems. A brief introduction on essential oil chemistry is presented to better understand the relationship of chemical aspects with the bioactivity of these products. Next, the antioxidant, anti-inflammatory, antitumor, and antimicrobial activities are discussed. The mechanisms of action against various types of viruses are also addressed. The data show that the multiplicity of pharmacological properties of essential oils occurs due to the chemical diversity in their composition and their ability to interfere with biological processes at cellular and multicellular levels via interaction with various biological targets. Therefore, these natural products can be a promising source for the development of new drugs. [ABSTRACT FROM AUTHOR]

Essential oils from Amazonian species are gaining increasing interest worldwide due to their medicinal and cosmetic applications; however, the relation among the chemical constituents and their biological properties are not well explored. Therefore, the present research aims to obtain an understanding of the bioactivity of chemical compounds in the essential oils of plants from the Annonaceae family (Bocageopsis pleiosperma, Onychopetalum amazonicum, Unonopsis duckei, U. floribunda, U. rufescens, U.stipitata, U. guatterioides, Duguetia flagellaris and Xylopia benthamii). By means of gas chromatography coupled to mass spectrometry, in vitro cytotoxic and anti-lipase assays, principal component analysis and molecular docking, it was possible to establish the main compounds that may be responsible for the cytotoxic effect of O. amazonicum and B. pleiosperma. Moreover, the anti-lipase potential of D. flagellaris was also established, as well as its composition related to the activity. Thus, by the employed strategy, allo-aromadendrene, cryptomerione, δ-cadinene and β-bisabolene were suggested as plausible cytotoxic agents against cancer cell lines, and dehydroaromadendrene, spathulenol and elemol, against lipase. The present study provides significant information on the chemical profile and bioactivity studies of Amazon Annonaceae aromatic plants. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a central role in the pathophysiology of melanoma. Curcumin (CUR) is a polyphenolic phytochemical that stimulates reactive oxygen species (ROS) production, while disulfiram (DSS) is a US FDA-approved drug for the treatment of alcoholism that can act by inhibiting the intracellular antioxidant system. Therefore, we hypothesized that they act synergistically against melanoma cells. Herein, we aimed to study the antitumor potential of the combination of CUR with DSS in B16-F10 melanoma cells using in vitro and in vivo models. The cytotoxic effects of different combination ratios of CUR and DSS were evaluated using the Alamar Blue method, allowing the production of isobolograms. Apoptosis detection, DNA fragmentation, cell cycle distribution, and mitochondrial superoxide levels were quantified by flow cytometry. Tumor development in vivo was evaluated using C57BL/6 mice bearing B16-F10 cells. The combinations ratios of 1:2, 1:3, and 2:3 showed synergic effects. B16-F10 cells treated with these combinations showed improved apoptotic cell death and DNA fragmentation. Enhanced mitochondrial superoxide levels were observed at combination ratios of 1:2 and 1:3, indicating increased oxidative stress. In vivo tumor growth inhibition for CUR (20 mg/kg), DSS (60 mg/kg), and their combination were 17.0%, 19.8%, and 28.8%, respectively. This study provided data on the potential cytotoxic activity of the combination of CUR with DSS and may provide a useful tool for the development of a therapeutic combination against melanoma. [ABSTRACT FROM AUTHOR]

Duguetia pycnastera Sandwith (Annonaceae) is a tropical tree that can be found in the Guyanas, Bolivia, Venezuela, and Brazil. In Brazil, it is popularly known as "ata", "envira", "envira-preta", and "envira-surucucu". In the present work, we investigated the in vitro and in vivo HepG2 cell growth inhibition capacity of D. pycnastera leaf essential oil (EO). The chemical composition of the EO was determined by GC–MS and GC–FID analyses. The alamar blue assay was used to examine the in vitro cytotoxicity of EO in cancer cell lines and non-cancerous cells. In EO-treated HepG2 cells, DNA fragmentation was measured by flow cytometry. The in vivo antitumor activity of the EO was assessed in C.B-17 SCID mice xenografted with HepG2 cells treated with the EO at a dosage of 40 mg/kg. Chemical composition analysis displayed the sesquiterpenes α-gurjunene (26.83%), bicyclogermacrene (24.90%), germacrene D (15.35%), and spathulenol (12.97%) as the main EO constituents. The EO exhibited cytotoxicity, with IC50 values ranging from 3.28 to 39.39 μg/mL in the cancer cell lines SCC4 and CAL27, respectively. The cytotoxic activity of the EO in non-cancerous cells revealed IC50 values of 16.57, 21.28, and >50 μg/mL for MRC-5, PBMC, and BJ cells, respectively. An increase of the fragmented DNA content was observed in EO-treated HepG2 cells. In vivo, EO displayed tumor mass inhibition activity by 47.76%. These findings imply that D. pycnastera leaf EO may have anti-liver cancer properties. [ABSTRACT FROM AUTHOR]

In this study, we report the synthesis of twenty new acridine–thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M−1; Ksv = 2.6 × 103 M−1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM. [ABSTRACT FROM AUTHOR]

Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a–r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel binuclear copper(II) complex was prepared. • This complex was confirmed by Synchrotron X-ray diffraction (SXRD). • Complex/CT-DNA interaction presents Kb of 1.6 × 104 L.mol−1. • Cytotoxic assays against HCT116 and HepG2 cells were carried out. • The complex showed higher levels of activated caspase-3 and cleaved PARP. A novel binuclear copper(II)-based complex was obtained with 2-(2,4-dihydroxybenzoyl)benzoate (DBB) and 1,10-phenanthroline (phen) as chelate ligands (Complex 1). Characterization was performed by ultraviolet, visible and infrared spectroscopy, and Synchrotron X-ray diffraction (SXRD), confirming the chemical structure. The crystal structure presents each metal center of complex 1 with a distorted square pyramidal geometry. Such as observed, one metal ion shows of one DBB and one phen as bidentate, as well as one monodentate methanol at the axial position. Meanwhile, the other copper center is also formed by one DBB and phen as bidentate ligands, and an additional carboxylate of DBB as monodentate, making a bridge between the two nuclei of the complex. Alamar blue assays revealed that complex 1 is cytotoxic against HCT116 (human colon carcinoma), and HepG2 (human hepatocellular carcinoma) tumor cell lines, with IC 50 values of 5 and 2.75 μg.mL−1, respectively. HCT116 cells treated with complex 1 showed higher levels of activated caspase-3 and cleaved PARP (Asp214), as well as higher DNA fragmentation. [ABSTRACT FROM AUTHOR]

Guatteria olivacea R. E. Fries (synonym Guatteria punctata (Aubl.) R.A. Howard) is a tree of 10–27 m tall popularly known as "envira-bobó", "envira-fofa", "envireira", "embira", "embira-branca", "embira-preta", envira-branca", and "envira-preta", which can be found in the Brazilian Amazon biome. In this study, we evaluated the cytotoxic and antitumor effects of the essential oil (EO) obtained from the leaves of G. olivacea against liver cancer using HepG2 cells as a model. EO was obtained using a hydrodistillation Clevenger-type apparatus and was qualitatively and quantitatively characterized using GC–MS and GC–FID, respectively. The alamar blue assay was used to assess the cytotoxic potential of EO in a panel of human cancer cell lines and human non-cancerous cells. In HepG2 cells treated with EO, YO-PRO-1/propidium iodide staining, cell cycle distribution, and reactive oxygen species (ROS) were examined. In C.B-17 SCID mice with HepG2 cell xenografts, the efficacy of the EO (20 and 40 mg/kg) was tested in vivo. GC–MS and GC–FID analyses showed germacrene D (17.65%), 1-epi-cubenol (13.21%), caryophyllene oxide (12.03%), spathulenol (11.26%), (E)-caryophyllene (7.26%), bicyclogermacrene (5.87%), and δ-elemene (4.95%) as the major constituents of G. olivacea leaf EO. In vitro cytotoxicity of EO was observed, including anti-liver cancer action with an IC50 value of 30.82 μg/mL for HepG2 cells. In HepG2 cells, EO treatment increased apoptotic cells and DNA fragmentation, without changes in ROS levels. Furthermore, the EO inhibited tumor mass in vivo by 32.8–57.9%. These findings suggest that G. olivacea leaf EO has anti-liver cancer potential. [ABSTRACT FROM AUTHOR]

Abstract: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC50 values in the nanomolar range. Cell cycle arrest in G2/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G2/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential. [Copyright &y& Elsevier]

Abstract: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) belongs to the phenstatin family. This compound has been studied due to its potent cytotoxicity and ability to inhibit tubulin assembly. The present study aimed to evaluate the mutagenic potential of PHT in human lymphocytes. PHT displayed cytotoxicity in human lymphocytes with an IC50 value of 5.68μM, and therefore, concentrations of 0.25, 0.5, 1.0, 2.0, and 4.0μM were used for all protocols. The alkaline comet assay and chromosome aberration (CA) analysis were performed in different phases of the cell cycle (G1, G1/S, transition, and G2), to evaluate the DNA-damaging and clastogenic effects of PHT, respectively. CA analysis was carried out in the presence or absence of colchicine to evaluate the action of PHT in the mitotic phase. PHT was cytotoxic and significantly reduced the mitotic index with drug exposure in all phases of cell cycle. Interestingly, it induced an increase in mitotic index in experimental protocols without colchicine, corroborating its action as an antitubulin agent. It also induced DNA damage and was clastogenic with drug exposure in all phases of the cell cycle, in the presence or absence of colchicine. In conclusion, PHT induces DNA damage and exerts clastogenic effects in human lymphocytes. [Copyright &y& Elsevier]

Duguetia A. St. Hill (Annonaceae) is recognized as one of the major genera with approximately 100 species, 67 of which are found in Brazil (29 of those are endemic). They are arboreal species with edible fruits known as "pindaíba", "pindaíva" "pinha", and "envira" in Brazil. Many Duguetia species, in particular, have been used in traditional medicine to treat renal colic, stomachache, rheumatism, cough, toothache, muscle pain, fever, gastrointestinal pain, and breathing difficulties. In this study, we reviewed the chemical constituents and pharmacological properties of essential oils (EOs) from Duguetia species. A total of 12 species were found, along with their EO chemical constituents and bioactivities. Bicyclogermacrene, humulene epoxide II, spathulenol, germacrene D, caryophyllene oxide, viridiflorene, α-pinene, β-caryophyllene, and β-pinene were the main chemical constituents reported. The pharmacological effects of Duguetia species EOs included anti-inflammatory, antinociceptive, antibacterial, antifungal, antioxidant, anti-trypanosoma, cytotoxic and antitumor properties. This information adds to our understanding of the potential of the EOs of Duguetia species. [ABSTRACT FROM AUTHOR]

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF 6 , to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs. [Display omitted] • RCT exhibits potent cytotoxicity to solid and haematological cancer cells. • RCT causes elimination of hepatic CSCs from HCC HepG2 cells. • RCT inhibits HCC HepG2 cell motility. • RCT suppresses Akt/mTOR signalling in HCC HepG2 cells. • RCT induces apoptotic and autophagic cell death in HCC HepG2 cells. [ABSTRACT FROM AUTHOR]

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression. [ABSTRACT FROM AUTHOR]

Abstract Carvacrol, a phenolic monoterpene derived from thyme oil has gained wide interest recently because of its anticancer activities. To improve the solubility of carvacrol, the formation of inclusion complexes with β-cyclodextrin was performed by ultrasound and freeze-drying methods and characterized using thermal analysis, FTIR, XRD, SEM, NMR and HPLC analysis. From these results, carvacrol was successfully complexed within β-cyclodextrin cavity. Moreover, HPLC analysis demonstrated a higher entrapment efficiency for freeze-drying method (81.20 ± 0.52%) in contrast to ultrasound method (34.02 ± 0.67%). Hence, freeze-drying inclusion complex was evaluated for its antiproliferative effect and cytotoxicity against prostate cancer cell line (PC3) in vitro. Further, freeze-drying complex led to a dose-dependent inhibition in tumor cell growth in 2D and 3D cell culture systems. Altogether, the inclusion of carvacrol in β-cyclodextrin led to the formation of stable complexes with potent antiproliferative effects against PC3 cells, in vitro. Such an improved cytotoxic effect can be attributed to the enhanced the aqueous solubility and bioavailability of carvacrol by effective complexation in β-cyclodextrin. Graphical abstract Image 1 Highlights • CARV/β-CD complexes have been developed to improve the anticancer activity. • The FD method showed high efficiency in the formation of inclusion complexes. • FD complexes enhanced in vitro anticancer activity and cytotoxicity against PC3. • FD complex also reduced the cell viability of PC3 encapsulated in GelMA hydrogels. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Salacia impressifolia (Miers) A. C. Smith (family Celastraceae) is a traditional medicinal plant found in the Amazon Rainforest known as "miraruíra", "cipó-miraruíra" or "panu" and is traditionally used to treat dengue, flu, inflammation, pain, diabetes, male impotency, renal affections, rheumatism and cancer. Aim of the study: The aim of this study was to investigate in vitro and in vivo anti-leukemia activity of the stem bark of S. impressifolia in experimental models. Materials and methods: The in vitro cytotoxic activity of extracts, fractions and quinonemethide triterpenes (22-hydroxytingenone, tingenone and pristimerin) from the stem bark of S. impressifolia in cultured cancer cells was determined. The in vivo antitumor activity of the ethyl acetate extract (EAE) and of its fraction (FEAE.3) from the stem bark of S. impressifolia was assessed in C.B-17 severe combined immunodeficient (SCID) mice engrafted with human promyelocytic leukemia HL-60 cells. Results: The extract EAE, its fraction FEAE.3, and quinonemethide triterpenes exhibited potent cytotoxicity against cancer cell lines, including in vitro anti-leukemia activity against HL-60 and K-562 cells. Moreover, extract EAE and its fraction FEAE.3 inhibited the in vivo development of HL-60 cells engrafted in C.B-17 SCID mice. Tumor mass inhibition rates were measured as 40.4% and 81.5% for the extract EAE (20 mg/kg) and for its fraction FEAE.3 (20 mg/kg), respectively. Conclusions: Ethyl acetate extract and its fraction from the stem bark of S. impressifolia exhibit in vitro and in vivo anti-leukemia activity that can be attributed to their quinonemethide triterpenes. These data confirm the ethnopharmacological use of this species and may contribute to the development of a novel anticancer herbal medicine. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

The chemical composition of V. pyrantha resin (VpR) and fractions (VpFr1–7 and VpWS) were assessed by LC-MS and NMR. Twenty-eight metabolites were identified, including 16 diterpenoids, seven nor-diterpenoids, one fatty acid, one bis-diterpenoid, one steroid, one flavonoid, and one triterpenoid. The pharmacological potential of VpR, VpFr1–7, and isolated compounds was assessed by determining their antioxidant, antimicrobial, and cytotoxic activities. VpFr4 (IC 50 = 205.48 ± 3.37 μg.mL−1) had the highest antioxidant activity, whereas VpFr6 (IC 50 = 842.79 ± 10.23 μg.mL−1) had the lowest. The resin was only active against Staphylococcus aureus (MIC 62.5 μg.mL−1) and Salmonella choleraesius (MIC and MFC 500 μg.mL−1), but fractions were enriched with antibacterial compounds. V. pyrantha resin and fractions showed great cytotoxic activity against HCT116 (IC 50 = 20.08 μg.mL−1), HepG2 (IC 50 = 20.50 μg.mL−1), and B16-F10 (12.17 μg.mL−1) cell lines. Multivariate statistical analysis was used as a powerful tool to pinpoint possible metabolites responsible for the observed activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Piplartine is an alkamide found in different Piper species and possesses several biological activities, including antiparasitic properties. Thus, the aim of the present study was to evaluate a series of 32 synthetic piplartine analogues against the Leishmania amazonensis promastigote forms and establish the structure-activity relationship and 3D-QSAR of these compounds. The antileishmanial effect of the compounds was determined using the MTT method. Most compounds were found to be active against L. amazonensis. Among 32 assayed derivatives, compound (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity (IC50 = 0.007 ± 0.008 μM, SI > 10), followed by benzyl 3,4,5-trimethoxybenzoate (IC50 = 0.025 ± 0.009 μM, SI > 3.205) and (E)-furfuryl 3-(3,4,5-trimethoxyphenyl)-acrylate (IC50 = 0.029 ± 0.007 μM, SI > 2.688). It was found that the rigid substituents contribute to increasing antiparasitic activity against L. amazonensis promastigotes. The presence of the unsaturated heterocyclic substituent in the phenylpropanoid chemical structure (furfuryl group) resulted in a bioactive derivative. Molecular simplification of benzyl 3,4,5-trimethoxybenzoate by omitting the spacer group contributed to the bioactivity of this compound. Furthermore, bornyl radical appears to be important for antileishmanial activity, since (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity. These results show that some derivatives studied would be useful as prototype molecules for the planning of new derivatives with profile of antileishmanial drugs. [ABSTRACT FROM AUTHOR]

A theoretical and experimental DFT study of the vibrational, structural and quantum properties of annomontine ( 1 ) and N -hydroxyannomontine ( 2 ) alkaloids using the B3LYP exchange-correlation functional with 6-311G (2d, p) basis set is presented. The theoretical geometry optimization data of the two structures were compared with the X-ray data of (1) in the associated literature and a conformational study is presented for both molecules, providing a good comprehension of the conformational stability. In addition, natural bond orbitals (NBOs), HOMO-LUMO energy gap and mapped molecular electrostatic potential surface (MEPS) calculations were also performed at the same calculation approach. The calculated UV spectra agreed well with the measured experimental data, with transitions assigned. The comparative IR studies confirmed the intramolecular hydrogen bonds of the conformations and the intermolecular hydrogen bonds of dimeric forms and also revealed several characteristic vibrations for the structures. Molecular docking studies with DNA Topoisomerase II-DNA complex showed binding free energies of −11.5 and −10.6 kcal/mol for 2 and 1 respectively, while for amsacrine, used for the treatment of leukemia, and doxorubicin, used for the treatment of breast cancer, bladder cancer, Kaposi's sarcoma, and acute lymphocytic leukemia, the presented binding free energies values are −10.0 and −9.9 kcal/mol respectively, revealing good bind affinities of the tested alkaloids with the complex. In vitro cytotoxicity assay revealed an expressive antitumor activity of N -hydroxyannomontine against human hepatocellular carcinoma cell line HepG2. [ABSTRACT FROM AUTHOR]

Herein, we used thymine (HThy) as a ligand to form two new ruthenium(ii) complexes with formula [Ru(PPh3)2(Thy)(bipy)]PF6 (1) and [Ru(Thy)(bipy)(dppb)]PF6 (2). The complexes were characterized by spectroscopic, spectrometric and X-ray crystallography analyses. Complexes 1 and 2 can interact with ctDNA presenting binding constants, Kb, of 0.4 and 1.2 × 103 M−1, respectively. Their cytotoxic activities towards tumor cell lines (B16-F10, HepG2, K562 and HL-60) and non-tumor cells (PBMCs) were evaluated using the Alamar blue assay. Complex 1 exhibits high cytotoxicity against tumor cells, showing IC50 values of 0.01 and 1.81 μM against the HL-60 and HepG2 cell lines, respectively. Therefore, compound 1 can be considered as a promising antitumor metallodrug. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) have been used as important pharmaceutical excipients for improve the physicochemical properties of the drugs of low solubility as the essential oil of Hyptis martiusii. This oil is important therapeutically, but the low solubility and bioavailability compromises your use. Therein, the aim of this study was to obtain and to characterize physico-chemically the samples obtained by physical mixture (PM), paste complexation (PC) and slurry complexation (SC) of the essential oil Hyptis martiusii (EOHM) in β-CD, and to compare the antibacterial and modulatory-antibiotic activity of products obtained and oil free. The physicochemical characterization was performed by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Karl Fischer titration. Additionally, the antibacterial tests were performed by microdilution technique. Thus, it was observed that the PM method showed low complexing capacity, unlike PC and SC in which it was observed the formation of inclusion complexes. In addition, the second stage of the TG/DTG curves showed that SC was the best method inclusion with mass loss of 6.9% over the PC that was 6.0%. The XRD results corroborate with the results above suggesting the formation of new solid phase and the SEM photomicrographs showed the porous surface of the samples PC and SC. The essential oil alone demonstrated an antibacterial and modulatory effect against the S. aureus and the Gram negative strain, respectively. However, the β-CD and the inclusion complex did not demonstrate any biological activity in the performed antibacterial assays. [ABSTRACT FROM AUTHOR]

Heteroleptic Cu(II) complexes with monoanionic 2-hydroxybenzophenones and diimines interact with DNA that may be a possible target to their cytotoxic against tumor cells, such as HCT116 and HepG2. [Display omitted] Here, we report four new heteroleptic Cu(II) complexes with the formula [Cu(bipy)(2H4MeBz)]NO 3 (1), [Cu(phen)(2H4MeBz)]NO 3 (2), [Cu(bipy)(2H4OcBz)]NO 3 (3) and [Cu(phen)(2H4OcBz)]NO 3 (4), where the ligands are 2-hydroxy-4-methoxybenzophenone (2H4MeBz), 2-hydroxy-4-(octyloxy)benzophenone (2H4OcBz), 2,2′-bipiridine (bipy) and 1,10-phenantroline (phen). All compounds present two bidentate ligands, a monoanionic 2-hydroxybenzophenone, forming a six-membered chelate ring and the diiminic ring forming a five-membered chelate ring, as well as one nitrate as counterion located at the axial position, as suggested by the crystal structure of complex 2. Complex/DNA interaction studies were also performed using spectroscopic titration (K b close to 104 M−1), viscosity, Hoechst 33258 competition, and circular dichroism, revealing a moderate interaction between them. Additionally, complexes 1 – 4 moderately interact with BSA (Bovine Serum Albumin). The compounds were evaluated against HCT116 (human colon carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cells and against MRC-5 (human lung fibroblast), a noncancer cells. The cytotoxic results suggest that complexes 2 and 4 are more cytotoxic than 1 and 3 , showing that the presence of phen ligand may play an important role in increasing the biological effect of the compounds. [ABSTRACT FROM AUTHOR]

Xylopia laevigata (Annonaceae), known locally as “meiú” or “pindaíba”, is widely used in folk medicine in Northeastern Brazil. In the present work, we performed phytochemical analyses of the stem of X. laevigata, which led to the isolation of 19 alkaloids: (–)-roemerine, (+)-anonaine, lanuginosine, (+)-glaucine, (+)-xylopine, oxoglaucine, (+)-norglaucine, asimilobine, (–)-xylopinine, (+)-norpurpureine, (+)-N-methyllaurotetanine, (+)-norpredicentrine, (+)-discretine, (+)-calycinine, (+)-laurotetanine, (+)-reticuline, (–)-corytenchine, (+)-discretamine and (+)-flavinantine. The in vitro cytotoxic activity toward the tumor cell lines B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), K562 (human chronic myelocytic leukemia) and HL-60 (human promyelocytic leukemia) and non-tumor peripheral blood mononuclear cells (PBMCs) was tested using the Alamar Blue assay. Lanuginosine, (+)-xylopine and (+)-norglaucine had the highest cytotoxic activity. Additionally, the pro-apoptotic effects of lanuginosine and (+)-xylopine were investigated in HepG2 cells using light and fluorescence microscopies and flow cytometry-based assays. Cell morphology consistent with apoptosis and a marked phosphatidylserine externalization were observed in lanuginosine- and (+)-xylopine-treated cells, suggesting induction of apoptotic cell death. In addition, (+)-xylopine treatment caused G2/M cell cycle arrest in HepG2 cells. These data suggest that X. laevigata is a potential source for cytotoxic alkaloids. [ABSTRACT FROM AUTHOR]

Annona vepretorum Mart. (Annonaceae), popularly known as 'bruteira', has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β-cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger-type apparatus and analysed using GC- MS and GC- FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16-F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), ( E)-β-ocimene (12.46%), α-phellandrene (8.08%), o-cymene (6.24%), germacrene D (3.27%) and α-pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%). [ABSTRACT FROM AUTHOR]

Aims The present study evaluated the carvacrol (CARV) effect on hyperalgesia and nociception induced by sarcoma 180 (S180) in mice. Main methods Carvacrol treatment (12.5–50 mg/kg s.c.) once daily for 15 days was started 24 h after injection of the sarcoma cells in the hind paw (s.c.). Mice were evaluated for mechanical sensitivity (von Frey), spontaneous and palpation-induced nociception, limb use and tumor growth on alternate days. CARV effects on the central nervous system were evaluated through immunofluorescence for Fos protein. Molecular docking studies also were performed to evaluate intermolecular interactions of the carvacrol and muscimol, as ligands of interleukin-10 and GABA A receptors. Key findings CARV was able to significantly reduce mechanical hyperalgesia and spontaneous and palpation-induced nociception, improve use paw, decrease the number of positively marked neurons in lumbar spinal cord and activate periaqueductal gray, nucleus raphe magnus and locus coeruleus . CARV also caused significant decreased tumor growth. Docking studies showed favorable interaction overlay of the CARV with IL-10 and GABA A. Significance Together, these results demonstrated that CARV may be an interesting option for the development of new analgesic drugs for the management of cancer pain. [ABSTRACT FROM AUTHOR]

This work describes a novel ent -kaurane diterpene, ent -3β-hydroxy-kaur-16-en-19-al along with five known ent -kaurane diterpenes, ent -3β,19-dihydroxy-kaur-16-eno, ent -3β-hydroxy-kaur-16-eno, ent -3β-acetoxy-kaur-16-eno, ent -3β-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, β-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent -kaurane diterpenes. Among them, e nt -3β-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC 50 of 2.49 μg/mL) and lower over B16-F10 cell line (IC 50 of 21.02 μg/mL). [ABSTRACT FROM AUTHOR]

ABSTRACT Guatteria blepharophylla Mart. (synonym Guatteriopsis blepharophylla Mart.) and Guatteria hispida (R.E. Fr.) Erkens & Maas (synonym Guatteriopsis hispida R.E. Fr.) belong to the Annonaceae family and are found in the Brazilian and Colombian Amazon basin. Both species are popularly known as 'envira' or 'envireira'. In the present study, the leaf essential oils of G. blepharophylla (EOGB) and G. hispida (EOGH) were selected to investigate their cytotoxic effects. Tumour cell lines were treated with increasing concentrations of both essential oils for 72 h and analysed by a methyl-[3H]thymidine incorporation assay. The pro-apoptotic effect of these essential oils was assessed in HepG2 cells by morphological analysis (using haematoxylin/eosin staining and acridine orange/ethidium bromide staining), flow cytometry (cell membrane integrity and internucleosomal DNA fragmentation analysis) and a caspase-3 activation assay after 24 h incubation. Both essential oils displayed potent cytotoxicity in different tumour cell lines. EOGB showed IC50 values from 6.03 to 16.46 µg/ml for HepG2 and K562 cell lines, and EOGH showed IC50 values from 5.45 to 24.89 µg/ml for HepG2 and K562 cell lines, respectively. Cell morphologies consistent with apoptosis and a remarkable activation of caspase-3 were observed in the HepG2 cells treated with essential oils for 24 h. Significant increases in internucleosomal DNA fragmentation without altered membrane integrity were also found. In conclusion, both essential oils investigated were able to inhibit tumour cell proliferation and induce cell death by apoptosis pathways. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Highlights: [•] The essential oil contains (E)-caryophyllene as its major component. [•] The essential oil displays cytotoxicity to tumour cell lines. [•] The essential oil possesses in vivo antitumour action. [ABSTRACT FROM AUTHOR]

Eudesmols are naturally occurring sesquiterpenoid alcohols that present cytotoxic effect to cancer cells. Herein, all eudesmol isomers displayed cytotoxicity to different tumour cell lines. α-Eudesmol showed IC50 values ranging from 5.38 ± 1.10 to 10.60 ± 1.33 μg/mL for B16- F10 and K562 cell lines, β-eudesmol showed IC50 values ranging from 16.51 ± 1.21 to 24.57 ± 2.75 μg/mL for B16- F10 and Hep G2 cell lines, and γ-eudesmol showed IC50 values ranging from 8.86 ± 1.27 to 15.15 ± 1.06 μg/mL for B16- F10 and K562 cell lines, respectively. In addition, in this work, we studied the mechanisms of cytotoxic action of eudesmol isomers (α-, β- and γ-eudesmol) in human hepatocellular carcinoma Hep G2 cells. After 24-hr incubation, Hep G2 cells treated with eudesmol isomers presented typical hallmarks of apoptosis, as observed by morphological analysis in cells stained with haematoxylin-eosin and acridine orange/ethidium bromide. None of eudesmol isomers caused membrane disruption at any concentration tested. Moreover, eudesmol isomers induced loss of mitochondrial membrane potential and an increase in caspase-3 activation in Hep G2 cells, suggesting the induction of caspase-mediated apoptotic cell death. In conclusion, the eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumour cell death by caspase-mediated apoptosis pathways. [ABSTRACT FROM AUTHOR]

Abstract: Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Himatanthus drasticus (Mart.) Plumel – Apocynaceae is a medicinal plant popularly known as Janaguba. Its bark and latex have been used by the public for cancer treatment, among other medicinal uses. However, there is almost no scientific research report on its medicinal properties. Aim of the study: The aim of this study was to investigate the antitumor effects of Himatanthus drasticus latex proteins (HdLP) in experimental models. Materials and methods: The in vitro cytotoxic activity of the HdLP was determined on cultured tumor cells. HdLP was also tested for its ability to induce lysis of mouse erythrocytes. In vivo antitumor activity was assessed in two experimental models, Sarcoma 180 and Walker 256 carcinosarcoma. Additionally, its effects on the immunological system were also investigated. Results: HdLP did not show any significant in vitro cytotoxic effect at experimental exposure levels. When intraperitoneally administered, HdLP was active against both in vivo experimental tumors. However, it was inactive by oral administration. The histopathological analysis indicates that the liver and kidney were only weakly affected by HdLP treatment. It was also demonstrated that HdLP acts as an immunomodulatory agent, increasing the production of OVA-specific antibodies. Additionally, it increased relative spleen weight and the incidence of megakaryocyte colonies. Conclusion: In summary, HdLP has some interesting anticancer activity that could be associated with its immunostimulating properties. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Himatanthus drasticus (Mart.) Plumel – Apocynaceae is a medicinal plant popularly known as Janaguba. Its bark and latex have been used by the public for cancer treatment, among other medicinal uses. However, there is almost no scientific research report on its medicinal properties. Aim of the study: The aim of this study was to investigate the antitumor effects of Himatanthus drasticus latex proteins (HdLP) in experimental models. Materials and methods: The in vitro cytotoxic activity of the HdLP was determined on cultured tumor cells. HdLP was also tested for its ability to induce lysis of mouse erythrocytes. In vivo antitumor activity was assessed in two experimental models, Sarcoma 180 and Walker 256 carcinosarcoma. Additionally, its effects on the immunological system were also investigated. Results: HdLP did not show any significant in vitro cytotoxic effect at experimental exposure levels. When intraperitoneally administered, HdLP was active against both in vivo experimental tumors. However, it was inactive by oral administration. The histopathological analysis indicates that the liver and kidney were only weakly affected by HdLP treatment. It was also demonstrated that HdLP acts as an immunomodulatory agent, increasing the production of OVA-specific antibodies. Additionally, it increased relative spleen weight and the incidence of megakaryocyte colonies. Conclusion: In summary, HdLP has some interesting anticancer activity that could be associated with its immunostimulating properties. [Copyright &y& Elsevier]

Abstract: Ten α-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10α-acetoxy-3-oxo-1,7αH,6,11βH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10α-hydroxy-3-oxo-1,7αH,6,11βH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using α-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of α-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7αH,6βH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7αH,6βH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10α-acetoxy-3-oxo-1,7αH,6βH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10α-acetoxy-3β-hydroxy-1,7αH,6,11βH-guai-4-en-6,12-olide (10) and 3β,10α-hydroxy-1,7αH,6,11βH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC50 values in the range of 0.36–14.5μM, showed as common structural feature the presence of an α-methylidene-γ-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development. [Copyright &y& Elsevier]

Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin , as a target for TG and 22-HTG. The application of N -acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin. • TG and 22-HTG induce caspase-mediated apoptotic cell death. • TG and 22-HTG target oxidative stress through downregulation of thioredoxin. • TG and 22-HTG cause DNA damage. • TG and 22-HTG cause JNK/p38-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study, we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [ b ]naphtho [2,1-d]furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC 50 values of 3.06 and 0.98 μM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using melanoma cells in a murine model in vivo , CNFD induced a potent anti-tumor activity. Herein, we describe, for the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy. • A new anti-tumor naphthoquinone (CNFD) are strongly cytotoxic and induces apoptosis. • The cytotoxicity can be mediated by an increase of ROS production. • CNFD cause loss of mitochondrial membrane potential and activation of caspases. • CNFD decrease B16F10 tumor in mice. [ABSTRACT FROM AUTHOR]

Diclinanona calycina R. E. Fries popularly known as "envira", is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of D. calycina was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in D. calycina as well as in the genus Diclinanona. The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (1); aporphine, anonaine (2); oxoaporphine, liriodenine (3); benzyltetrahydroisoquinolines, (S)-(+)-reticuline (4); dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (5); (+)-1S,2R-reticuline Nβ-oxide (6); and (+)-1S,2S-reticuline Nα-oxide (7); tetrahydroprotoberberine, coreximine (8); and pavine, bisnorargemonine (9). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (10), dichamanetin (11), and a mixture of uvarinol (12) and isouvarinol (13). Compound 5 is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (10), and the mixture of uvarinol (12) and isouvarinol (13), which presented moderate cytotoxic activity against the tested cancer cell lines (<20.0 µg·mL−1) and low cytotoxicity against the non-cancerous cell line MRC-5 (>25.0 µg·mL−1). Dichamanetin (11) showed cytotoxic activity against HL-60 and HCT116 with IC50 values of 15.78 µg·mL−1 (33.70 µmol·L−1) and 18.99 µg·mL−1 (40.56 µmol·L−1), respectively while the mixture of uvarinol (12) and isouvarinol (13) demonstrated cytotoxic activity against HL-60, with an IC50 value of 9.74 µg·mL−1, and HCT116, with an IC50 value of 17.31 µg·mL−1. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound. [ABSTRACT FROM AUTHOR]

• Homo-Lumo energy gap and global reactive parameters were calculated. • MEP, ALIE and Fukui indices calculations indicate the most reactive regions of the alkaloids guadiscine and guadiscidine. • The comparison between theoretical and experimental IR spectra allowed to visualize intermolecular H-Bonds formation through dimer formation. • Solvation free energies were calculated in different solvents. • Cytotoxicity assay performed with guadiscidine revealed great activity against HepG2 cell line. In this study, guadiscine (G1) and guadiscidine (G2), 7,7-dimethylaporphine alkaloids from Guatteria friesiana , have they geometric paramaters, vibrational behavior and quantum chemical properties (HOMO-LUMO, MEP, ALIE and Fukui indices) analyzed through a theoretical view, by density functional theory (DFT), using the Becker's three-parameter hybrid exchange functional combined with the Lee–Yang–Parr correlation functional (B3LYP) and 6–311G(2d,p) and 6–311G++(2df,3p) basis sets. The obtained geometry data were compared with x-ray data for (−)- N -acetyl-anonaine, showing close values. Vibrational analysis, together with potential energy distribution (PED) calculations, revealed several characteristic vibrations that characterize the 7,7 dimethylaporphine skeleton, besides enabling the observation of intermolecular H-bonds through dimers formation. Molecular dynamic simulations were carried out, allowing to evaluate the solvation free energies of G1 and G2 in water, methanol and ethanol, as well as H-bonds formation between G1 and G2 and the tested solvents. The antineoplastic potential of the title molecules was evaluated via molecular docking calculations with topoisomerase I complexed with DNA. Guadiscine and guadiscidine showed, respectively, binding free energies of -8.0 and -8.5 kcal/mol, while topotecan, a DNA topoisomerase I inhibitor, showed a binding free energy value of -12 kcal/mol, indicating that the studied molecules are good topoisomerase I inhibitors. In vitro cytotoxicity assay with HepG2 cell line were performed, revealing significant antitumor potential for G2. [ABSTRACT FROM AUTHOR]

• Acute myeloid leukemia remains the most lethal of leukemias. • Leukemic stem cells are associated with disease relapses. • Cell signaling pathways are targets to eliminate AML stem cells. Acute myeloid leukemia (AML) remains the most lethal of leukemias and a small population of cells called leukemic stem cells (LSCs) has been associated with disease relapses. Some cell signaling pathways play an important role in AML survival, proliferation and self-renewal properties and are abnormally activated or suppressed in LSCs. This includes the NF-κB, Wnt/β-catenin, Hedgehog, Notch, EGFR, JAK/STAT, PI3K/AKT/mTOR, TGF/SMAD and PPAR pathways. This review aimed to discuss these pathways as molecular targets for eliminating AML LSCs. Herein, inhibitors/activators of these pathways were summarized as a potential new anti-AML therapy capable of eliminating LSCs to guide future researches. The clinical use of cell signaling pathways data can be useful to enhance the anti-AML therapy. [ABSTRACT FROM AUTHOR]

Virola surinamensis (Rol. ex Rottb.) Warb. (Myristicaceae), popularly known in Brazil as "mucuíba", "ucuúba", "ucuúba-branca" or "ucuúba do igapó", is a medicinal plant used to treat a variety of diseases, including infections, inflammatory processes and cancer. In the present work, we investigated the chemical constituents and the in vitro and in vivo inhibition of human colon carcinoma HCT116 cells by essential oils obtained from the bark (EOB) and leaves (EOL) of V. surinamensis. EOB and EOL were obtained by hydrodistillation and analyzed via gas chromatography with flame ionization detection and gas chromatography coupled to mass spectrometry. In vitro cytotoxic activity was determined in cultured cancer cells HCT116, HepG2, HL-60, B16–F10 and MCF-7 and in a non-cancerous cell line MRC-5 by the Alamar blue assay after 72 h of treatment. Annexin V/propidium iodide staining, mitochondrial transmembrane potential and cell cycle distribution were evaluated by flow cytometry in HCT116 cells treated with essential oils after 24 and 48 h of treatment. The cells were also stained with May-Grunwald-Giemsa to analyze cell morphology. In vivo antitumor activity was evaluated in C.B-17 SCID mice with HCT116 cells. The main constituents in EOB were aristolene (28.0 ± 3.1%), α-gurjunene (15.1 ± 2.4%), valencene (14.1 ± 1.9%), germacrene D (7.5 ± 0.9%), δ-guaiene (6.8 ± 1.0%) and β-elemene (5.4 ± 0.6%). On the other hand, EOL displayed α-farnesene (14.5 ± 1.5%), β-elemene (9.6 ± 2.3%), bicyclogermacrene (8.1 ± 2.0%), germacrene D (7.4 ± 0.7%) and α-cubebene (5.6 ± 1.1%) as main constituents. EOB showed IC 50 values for cancer cells ranging from 9.41 to 29.52 μg/mL for HCT116 and B16–F10, while EOL showed IC 50 values for cancer cells ranging from 7.07 to 26.70 μg/mL for HepG2 and HCT116, respectively. The IC 50 value for a non-cancerous MRC-5 cell was 34.7 and 38.93 μg/mL for EOB and EOL, respectively. Both oils induced apoptotic-like cell death in HCT116 cells, as observed by the morphological characteristics of apoptosis, externalization of phosphatidylserine, mitochondrial depolarization and fragmentation of internucleosomal DNA. At a dose of 40 mg/kg, tumor mass inhibition rates were 57.9 and 44.8% in animals treated with EOB and EOL, respectively. These data indicate V. surinamensis as possible herbal medicine in the treatment of colon cancer. Image 1 [ABSTRACT FROM AUTHOR]

Simple Summary: Autophagy is a physiological process characterized by the degradation of the cell components through lysosomes due to stimuli/stress. In this study, we review the challenges and therapeutic opportunities that autophagy presents in the treatment of cancer. We discussed the results of several studies that evaluated autophagy as a therapeutic strategy in cancer, both through the modulation of therapeutic resistance and the death of cancer cells. Moreover, we discussed the role of autophagy in the biology of cancer stem cells and the inhibition of this process as a strategy to overcome resistance and progression of cancer stem cells. Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed. [ABSTRACT FROM AUTHOR]