Chemical composition and cytotoxic activity of Garcinia atroviridis Griff. ex T. Anders. essential oils in combination with tamoxifen

Garcinia atroviridis Griff. ex T. Anders. is used as a medication agent in folkloric medicine. The present study was to examine the chemical composition of the stem bark and leaf of G. atroviridis as well as their cytotoxic effects against MCF-7 cells. The constituents obtained by hydrodistillation were identified using GC-MS. The stem bark oil (EO-SB) composed mainly the palmitoleic acid (51.9%) and palmitic acid (21.9%), while the leaf oil (EO-L) was dominated by (E)-β-farnesene (58.5%) and β-caryophyllene (16.9%). Treatment of MCF-7 cells using EO-L (100 μg/mL) caused more than 50% cell death while EO-SB did not induce cytotoxic effect. EO-L has stimulated the growth of BEAS-2B normal cells, but not in MCF-7 cancerous cells. The IC₅₀ of EO-L in MCF-7 and BEAS-2B cells were 71 and 95 μg/mL, respectively. A combination treatment of EO-L and tamoxifen induced more cell death than the treatment with drug alone at lower doses.     

Inhibition of cell proliferation by a resveratrol analog in human pancreatic and breast cancer cells

Resveratrol has been reported to possess cancer preventive properties. In this study, we analyzed anti-tumor activity of a newly synthesized resveratrol analog, cis-3,4'',5-trimethoxy-3''-hydroxystilbene (hereafter called 11b) towards breast and pancreatic cancer cell lines. 11b treatments reduced the proliferation of human pancreatic and breast cancer cells, arrested cells in the G2/M phase, and increased the percentage of cells in the subG1/G0 fraction. The 11b treatments also increased the total levels of mitotic checkpoint proteins such as BubR1, Aurora B, Cyclin B, and phosphorylated histone H3. Mechanistically, 11b blocks microtubule polymerization in vitro and it disturbed microtubule networks in both pancreatic and breast cancer cell lines. Computational modeling of the 11b-tubulin interaction indicates that the dimethoxyphenyl group of 11b can bind to the colchicine binding site of tubulin. Our studies show that the 11b treatment effects occur at lower concentrations than similar effects associated with resveratrol treatments and that microtubules may be the primary target for the observed effects of 11b. These studies suggest that 11b should be further examined as a potentially potent clinical chemotherapeutic agent for treating pancreatic and breast cancer patients.     

cNGR-based synergistic-targeted NIR fluorescent probe for tracing and bioimaging of pancreatic ductal adenocarcinoma

Identification of fluorescent biomarkers with peptide ligand-directed receptors for diagnosis or theranostic of pancreatic ductal adenocarcinoma (PDAC) is still challenging. As potential prognostic/predictive bioimaging targets, both aminopeptidase N (APN, known as CD13) and Caveolin-1 are found as upregulation on the cell membrane surface of PDAC, in which APN is the principal receptor of the cyclic peptide cNGR (Asn-Gly-Arg, NGR) and Caveolin-1 can synergistically mediate endocytosis in this receptor-targeted process. Herein, we conjugate cNGR to dicyanomethylene-4H-pyran (DCM) chromophore to develop a synergistic-targeted near-infrared (NIR) fluorescent probe DCM-cNGR with strongly intrinsic NIR fluorescence, stable optical performance, low cytotoxicity, and rapid accumulation in PANC-1 cells with the synergistic overexpressed APN receptor-targeted and Caveolin-1-mediated endocytosis. As demonstrated, DCM-cNGR can realize noninvasive NIR imaging for targeting PANC-1 tumor in vivo after intravenous injection into PANC-1 xenograft tumor of nude mice, making a great promise to improve the precision diagnosis and therapy of pancreatic cancer with real time tracing and bioimaging of PDAC in vitro and in vivo.     

Regioselective synthesis and structures of anti-cancer 20(R)-ginsenoside Rg3 derivatives

Abstract

Regioselective synthesis of three novel palmitates of 20(R)-ginsenoside Rg₃ was accomplished via a facile strategy, along with complete assignment of their ¹H and ¹³C NMR resonances by 1D and 2D NMR (¹H-¹H COSY, DEPT 135, HSQC, HMBC, and NOESY) techniques. The derivatives were tested for in vitro anti-proliferative activities against pancreatic cancer PANC-1 cells. Compounds 2, 3, and 4 exhibited more potent activity than did 20(R)-ginsenoside Rg₃.     

Ability of simple organotin polyethers to inhibit pancreatic cancer

A wide variety of organotin polyethers derived from the interfacial polymerization of dibutyltin dichloride and non-cancer inhibitory diols show decent to good inhibition of two human pancreatic cancer cell lines. In view of the general lack of ability of tested compounds to inhibit pancreatic cancer cell lines, this is significant. These cell lines are the AsPC-1 pancreatic cancer cell line which is an adenocarcinoma pancreatic cell line and the PANC-1 pancreatic cancer cell line which is an epithelioid carcinoma pancreatic cell line. The dibutyltin polyethers generally both exhibit EC₅₀ values in the same range and lower than cisplatin and higher CI₅₀ values than cisplatin. Essentially all of the polymers derived from simple non-aromatic diols showed CI₅₀ values greater than 2.     

Ultrasound mediated synthesis of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives and their pharmacological evaluation

Designed as potential cytotoxic agents a series of 6-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinoline derivatives were synthesized by using a Bischler type reaction. The methodology involved the cyclodehydration of 2-(3,4-dihydroquinolin-1(2H)-yl)-1-alkyl/aryl ethanones in the presence of p-TSA under ultrasound irradiation. A number of compounds were prepared using this methodology and tested for their in vitro anti-proliferative properties against cancer (leukemia) and non-cancerous cell lines. Some of the compounds showed promising and selective cytotoxic effects toward leukemia cells.     

Hetaryl- and heteroarylvinyl-substituted nitrofurans identified as non-cytotoxic selective antitubercular agents

New (E)-5-[2-(5-nitrofuran-2-yl)vinyl]-1,2,4-oxadiazoles and 5-(5-nitrofuran-2-yl)-1,2,4-oxadiazoles were synthesized via the base-promoted condensation of nitrofuran-containing acyl chlorides with amidoximes. Testing these compounds against Gram-negative E. coli, Gram-positive B. subtilis and S. aureus as well as M. tuberculosis HRv37 strain revealed three compounds being selectively antimycobacterial. None of these compounds displayed any cytotoxicity towards human pancreatic epithelioid carcinoma cell line, PANC-1.     

Determination of 5-fluorouracil and 5-fluoro-2'-deoxyuridine-5'-monophosphate in pancreatic cancer cell line and other biological materials using capillary electrophoresis

Capillary zone electrophoresis (CZE) was used for the rapid determination of 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) in pancreatic cancer cell line (PANC-1), culture medium, plasma and pancreatic tissue. The assay is based upon protein precipitation with acetonitrile followed by a 9-min CZE analysis of the supernatant in an uncoated fused-silica capillary employing a borate buffer and on-column absorbance detection at 265 nm. Using 50 microl of sample, 5-FU levels between 4.12 and 132 microg/ml (31.7-1000 microM) were found to provide linear calibration graphs. Intra-day and inter-day RSD values evaluated from peak height ratios (n=5) were <7.6 and <8.8%, respectively. Corresponding RSD values of detection times (n=7) were <1 and <1.5%, respectively. The limits of detection for 5-FU and FdUMP were 1.72 and 5.29 microg/ml, respectively. As application, the accumulation of 5-FU by PANC-1 cells over a 4-h time period was investigated. Having a culture medium concentration of 100 microg/ml, the 5-FU cell content was estimated to become equal to that of the surrounding medium (i.e., 100 microg/ml or 3.61 fmol per cell with a volume of 4.7 pl) within that time period. The sensitivity of the assay was sufficient for the determination of 5-FU in all cell samples. FdUMP, however, could not be detected in these samples. Furthermore, the data obtained in uncoated capillaries are compared to those measured in a fused-silica capillary whose inner surface was coated with linear polyacrylamide (about 10-fold reduction of electroosmosis). The latter capillary format was found to be useless for simultaneous analysis of 5-FU and FdUMP in pancreatic cells but could be potentially useful for analysis of these compounds in plasma.     

Design,Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC₅₀ values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC₅₀ value of 77.02 nM (compare to sorafenib: IC₅₀ = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects.     

Antioxidant and Anti-Proliferative Activity of Essential Oil and Main Components from Leaves of Aloysia polystachya Harvested in Central Chile

The aim of this study was to determine, first, the chemical composition of Aloysia polystachya (Griseb) Moldenke essential oil, from leaves harvested in central Chile; and second, its antioxidant and cytotoxic activity. Eight compounds were identified via gas chromatography–mass spectrometry (GC–MS) analyses, with the most representative being R-carvone (91.03%), R-limonene (4.10%), and dihydrocarvone (1.07%). For Aloysia polystachya essential oil, antioxidant assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), H₂O₂, ferric reducing antioxidant power (FRAP), and total reactive antioxidant potential (TRAP)) showed good antioxidant activity compared to commercial antioxidant controls; and anti-proliferative assays against three human cancer cell lines (colon, HT-29; prostate, PC-3; and breast, MCF-7) determined an IC₅₀ of 5.85, 6.74, and 9.53 µg/mL, and selectivity indices of 4.75, 4.12, and 2.92 for HT-29, PC-3, and MCF-7, respectively. We also report on assays with CCD 841 CoN (colon epithelial). Overall, results from this study may represent, in the near future, developments for natural-based cancer treatments.     

The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells

Our quest to isolate and characterize natural products with in vitro solid tumor selectivity is driven by access to repositories of Indo-Pacific sponge extracts. In this project an extract of a species of Haplosclerida sponge obtained from the US NCI Natural Products Repository displayed, by in vitro disk diffusion assay (DDA) and IC₅₀ determinations, selective cytotoxicity with modest potency to a human pancreatic cancer cell line (PANC-1) relative to the human lymphoblast leukemia cell line (CCRF-CEM). Two brominated indoles, the known 6-bromo conicamin (1) and the new derivative, 6-Br-8-keto-conicamin A (2), were identified and 2 (IC₅₀ 1.5 μM for the natural product vs 4.1 μM for the synthetic material) was determined to be responsible for the cytotoxic activity of the extract against the PANC-1 tumor cell line. The new natural product and ten additional analogs were prepared for further SAR testing.     

Anticarcinogenic and Antioxidant Action of an Edible Aquatic Flora Jussiaea repens L. Using In Vitro Bioassays and In Vivo Zebrafish Model

Oxidative stress is the major cause of many health conditions, and regular consumption of antioxidants helped to encounter and prevent such oxidative stress-related diseases. Due to safety concerns over long-term uses of synthetic antioxidants, natural antioxidants are more preferred. The purpose of this study is to investigate the antioxidant and anticancer activities of Jussiaea repens L., a wild edible flora found in Manipur, India. The antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), Ferric reducing antioxidant power (FRAP) assay and DNA-nicking assay. The anticancer activity was tested using five cancer lines viz., SKOV3 cells (ovarian), HeLa (cervical), MDA-MB-231 (breast), PANC-1 (pancreatic), and PC3 (prostate). The toxicity, developmental effect, antiproliferative activity was further tested using zebrafish embryos. The methanolic plant extract had higher polyphenol content than flavonoids. The in vitro study demonstrated a promising antioxidant capacity and DNA protection ability of this plant. The extract also showed cytotoxic activity against SKOV3, HeLa, MDA-MB-23, and PANC-1 cancer cell lines. The in vivo studies on zebrafish embryos demonstrated the extract’s ability to suppress the developmental process and elicited more cytotoxicity to cancer cells than developing zebrafish embryos. Moreover, the in vivo studies on zebrafish embryos also indicated the antiproliferative activity of J. repens L. extract.     

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2–15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC₅₀ values using an MTT assay.     

Ziziphus nummularia Attenuates the Malignant Phenotype of Human Pancreatic Cancer Cells: Role of ROS

Pancreatic cancer (PC) is the fourth leading cause of all cancer-related deaths. Despite major improvements in treating PC, low survival rate remains a major challenge, indicating the need for alternative approaches, including herbal medicine. Among medicinal plants is Ziziphus nummularia (family Rhamnaceae), which is a thorny shrub rich in bioactive molecules. Leaves of Ziziphus nummularia have been used to treat many pathological conditions, including cancer. However, their effects on human PC are still unknown. Here, we show that the treatment of human pancreatic ductal adenocarcinoma cells (Capan-2) with Ziziphus nummularia ethanolic extract (ZNE) (100–300 μg/mL) attenuated cell proliferation in a time- and concentration-dependent manner. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated the anti-proliferative effect of ZNE. In addition, ZNE significantly decreased the migratory and invasive capacity of Capan-2 with a concomitant downregulation of integrin α₂ and increased cell–cell aggregation. In addition, ZNE inhibited in ovo angiogenesis as well as reduced VEGF and nitric oxide levels. Furthermore, ZNE downregulated the ERK1/2 and NF-κB signaling pathways, which are known to drive tumorigenic and metastatic events. Taken together, our results suggest that ZNE can attenuate the malignant phenotype of Capan-2 by inhibiting hallmarks of PC. Our data also provide evidence for the potential anticancer effect of Ziziphus nummularia, which may represent a new resource of novel anticancer compounds, especially ones that can be utilized for the management of PC.     

N(4)-tolyl-2-benzoylpyridine-derived thiosemicarbazones and their palladium(II) and platinum(II) complexes: Cytotoxicity against human solid tumor cells

Complexes [Pt(2Bz4oT)Cl], [Pt(2Bz4mT)Cl], and [Pt(2Bz4pT)Cl] were prepared with N(4)-ortho-(H2Bz4oT), N(4)-meta-(H2Bz4mT), and N(4)-para-(H2Bz4pT) tolyl-2-benzoylpyridine-derived thiosemicarbazones. The thiosemicarbazones exhibited moderate anti-proliferative activity against HepG2 (hepatoma) and UACC-62 (melanoma) cancer cell lines, but showed high anti-proliferative effect against A431 (epithelial carcinoma) cancer cell lines. Upon coordination to platinum(II) the anti-proliferative activity decreases in all cases. The cytotoxicity of the previously prepared palladium(II) analogues [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] was also investigated. As in the case of the platinum(II) complexes, coordination to palladium(II) did not lead to activity improvement. Investigations on the mechanism of cytotoxic action against A431 cells revealed that [Pd(2Bz4oT)Cl] induced DNA fragmentation and apoptosis while H2Bz4oT did not present this effect. The high anti-proliferative effect of the thiosemicarbazones and [Pd(2Bz4oT)Cl] against A431 cells, together with the pro-apoptotic effect of [Pd(2Bz4oT)Cl] suggests that these compounds have potential as chemotherapeutic drug candidates.     

Rakicidins G - I,cyclic depsipeptides from marine Micromonospora chalcea FIM 02-523

Rakicidins G-I (1–3), three new cyclic depsipeptides including a long aliphatic chain without terminal methyl branching were isolated from culture broth of Micromonospora chalcea FIM 02–523, along with rakicidin E (4). Their structures were elucidated by extensive NMR and HR-ESI-MS analyses. Compounds 1–4 were evaluated for their cytotoxic activities against HCT-8 and PANC-1 human tumor cell lines under the hypoxic and normoxic conditions. They were approximately 18.2–20.3-fold more cytotoxic under hypoxic than under normoxic conditions on PANC-1, and compared with 7.4–8.7-fold more cytotoxic under hypoxic than under normoxic conditions on HCT-8. Meanwhile, compounds 1–3 were also tested inhibitory activities against gram positive anaerobic bacteria and the results exhibited MIC values in the range of 0.125–8?μg/mL.     

Novel Semi-Synthetic Cu (II)–Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)–cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.     

New Steroidal Saponins Isolated from the Rhizomes of Paris mairei

The genus Paris is an excellent source of steroidal saponins that exhibit various bioactivities. Paris mairei is a unique species and has been widely used as folk medicine in Southwest China for a long time. With the help of chemical methods and modern spectra analysis, five new steroidal saponins, pamaiosides A–E (1–5), along with five known steroidal saponins 6–10, were isolated from the rhizomes of Paris mairei. The cytotoxicity of all the new saponins was evaluated against human pancreatic adenocarcinoma PANC-1 and BxPC3 cell lines.