Composition and in vitro cytotoxic activities of essential oil of Hedychium spicatum from different geographical regions of western Himalaya by principal components analysis

The rhizome of Hedychium spicatum has been widely used in traditional medicines. The present study deals with the evaluation of the cytotoxic potential of rhizome essential oils from four different regions of the Western Himalaya (India) along with comparative correlation analysis to characterise the bioactive cytotoxic component. The essential oils were coded as MHS-1, MHS-2, MHS-3 and MHS-4, and characterised using GC-FID and GC–MS. The main volatile compounds identified were 1,8-cineol, eudesmol, cubenol, spathulenol and α-cadinol. In vitro cytotoxic activities were assessed against human cancer cell lines such as, the lung (A549), colon (DLD-1, SW 620), breast (MCF-7, MDA-MB-231), head and neck (FaDu), and cervix (HeLa). MHS-4 is significantly active in comparison to other samples against all cancer cell lines. Sample MHS-4 has major proportion of monoterpene alcohol mainly 1,8-cineol. Principal components analysis was performed for the experimental results and all four samples were clustered according to their percentage inhibition at different doses.     

Oplopanphesides A-C, three new phenolic glycosides from the root barks of Oplopanax horridus

Three new phenolic glycosides, named oplopanphesides A-C (1-3), have been isolated from the root barks of Oplopanax horridus. Their structures were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR techniques. These phenolic glycosides possess a novel feature in their sugar moieties that a 3-hydroxy-3-methylglutaryl moiety was connected with C-6 of the β-D-glucopyranosyl group. Those compounds showed no cytotoxic effects against human cancer cell lines (MDA-231 and MCF-7) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method.     

New 1,3,4-Thiadiazole Derivatives with Anticancer Activity

We designed and synthesized the 1,3,4-thiadiazole derivatives differing in the structure of the substituents in C2 and C5 positions. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and normal cell line (fibroblasts). The results showed that in both breast cancer cell lines, the strongest anti-proliferative activity was exerted by 2-(2-trifluorometylophenylamino)-5-(3-methoxyphenyl)-1,3,4-thiadiazole. The IC₅₀ values of this compound against MCF-7 and MDA-MB-231 breast cancer cells were 49.6 µM and 53.4 µM, respectively. Importantly, all new compounds had weaker cytotoxic activity on normal cell line than on breast cancer cell lines. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds. The most likely mechanism of action for the new compounds is connected with the activities of Caspase 3 and Caspase 8 and activation of BAX proteins.     

Three new phenanthrenes from Cremastra appendiculata (D. Don) Makino

Three new phenanthrenes,along with one known phenanthrene,were isolated from the ethanolic extract of the tubers of Cremastra appendiculata(D.Don) Makino.Their structures were elucidated on the basis of extensive spectroscopic analysis.Compounds 1-4 were tested for in vitro cytotoxic activities against human lung(A549),colon(HCT-116),liver(HepG2),and breast(MCF-7 and MDA-MB-231) cancer cell lines.     

Sartoryglabrins, analogs of ardeemins, from Neosartorya glabra

Chemical investigation of a collection of the fungus Neosartorya glabra from Thailand furnished sartoryglabins A-C (1a, 1b and 2) which are analogs of the reverse prenylated indole alkaloids known as (-) ardeemins. Structures of these compounds were established by NMR spectrometry and an X-ray analysis. Sartoryglabins A-C were evaluated for their in vitro growth inhibitory activity on three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma). All the compounds exhibited strong to moderate activity against the MCF-7 cell line but weak or no activity against the NCI-H460 and A375-C5 cell lines. Sartoryglabin B was found to exhibit selectivity towards the MCF-7 cell line.     

Lignans and Triterpenes from the Root of Pseuderanthemum carruthersii var. atropurpureum

Two new lignans, pseuderesinol (1), pseuderanoside (2) and a new triterpene, pseuderanic acid (3) were isolated from the dried root of Pseuderanthemum carruthersii (SEEM.) GUILL. var. atropurpureum (BULL.) FOSB. (Acanthaceae), together with ten known compounds, including five lignans, (+)-eudesmin (4), (+)-magnolin (5), (+)-syringaresinol (6), (+)-episyringaresinol (7), (+)-1-hydroxysyringaresinol (8) and five triterpenes, squalene (9), oleanolic acid (10), lupeol (11), betulin (12), betulinic acid (13). Their chemical structures were elucidated by 1D- and 2D-NMR, computational quantum chemistry, as well as high resolution-electrospray ionization (HR-ESI)-MS spectroscopic analysis. The acetylcholinesterase inhibition and cytotoxic activities against HeLa and MCF-7 cancer cell lines were evaluated on some purified compounds at the concentration of 100?μg/mL. Pseuderesinol (1) and magnolin (5) exhibited moderate cytotoxic activities against the MCF-7 cancer cell line.     

Synthesis and characterisation of estrogenic carriers for cytotoxic Pt(II) fragments: biological activity of the resulting complexes

This paper describes the synthesis and the spectroscopic characterisation of cis-dichloro[N-(4-(17alpha-ethynylestradiolyl)-benzyl)-ethylenediamine]platinum(II) and cis-diamino[2-(4-(17alpha-ethynylestradiolyl)-benzoylamino)-malonato]platinum(II). These complexes were synthesised in good yield according to multi-step procedures based on the classical and non-classical Sonogashira coupling reaction, respectively. These compounds retain an acceptable degree of relative binding affinity (RBA) for the alpha form of estrogen receptor. Combined treatment of breast cancer cell lines, namely hormone-sensitive MCF-7 and hormone-insensitive MDA-MB-231 cell lines, indicates that these compounds maintain agonistic activity so that the potential advantage in vehiculation of the cytotoxic moiety by means of the receptor system is counteracted by the proliferative effect of the estrogenic component of the entire molecule, especially at low concentrations.     

In vitro cytotoxic evaluation of a novel phosphinyl derivative of boldine

2,9-Dimethoxymethylboldine (2), 2,9-dimethoxymethyl-3-bromoboldine (3) and 2,9-dimethoxymethyl-3-diphenylphosphinylboldine (4) have been synthesized in an effort to find compounds with potential pharmacological applications. The cytotoxic activities of the natural precursor 1 and these three derivatives have been measured as IC?? inhibitory growth. The diphenylphosphinyl derivative 4 showed a significant cytotoxic activity on two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC?? values of 55.5 and 62.7 [μM], respectively. These results suggest that the kind of structural modifications introduced to synthesize compound 4 represent a promising way to enhance the cytotoxic activity of boldine derivatives.     

Down-regulation of Bcl-2 and Akt induced by combination of photoactivated hypericin and genistein in human breast cancer cells

Presented experiment considers combination of genistein and photodynamic therapy with hypericin with a view to achieve higher therapeutic outcome in human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, both identified in our conditions as photodynamic therapy resistant. Since genistein is known to suppress Bcl-2 expression, we predicted that photodynamic therapy with hypericin might benefit from mutual therapeutic combination. In line with our expectations, combined treatment led to down-regulation of Bcl-2 and up-regulation of Bax in both cell lines as well as to suppression of Akt and Erk1/2 phosphorylation induced by photoactivated hypericin in MCF-7 cells. Although Akt and Erk1/2 phosphorylation was not stimulated by photodynamic therapy with hypericin in MDA-MB-231 cells, it was effectively suppressed in combination. Variations in cell death signaling favoring apoptosis were indeed accompanied by cell cycle arrest in G₂/M-phase, activation of caspase-7, PARP cleavage and increased occurrence of cells with apoptotic morphology of nucleus. All these events corresponded with suppression of proliferation and significantly lowered clonogenic ability of treated cells. In conclusion, our results indicate that pre-treatment with tyrosine kinase inhibitor genistein may significantly improve the effectiveness of photodynamic therapy with hypericin in MCF-7 and MDA-MB-231 breast cancer cells.     

Evening Primrose Oil Enhances Tamoxifen’s Anticancer Activity against Breast Cancer Cells by Inducing Apoptosis,Inhibiting Angiogenesis,and Arresting the Cell Cycle

Background: Despite advancements in cancer treatment, breast cancer (BC) is still one of the leading causes of death among women. The majority of anti-breast-cancer medications induce serious side effects and multidrug resistance. Although several natural compounds, such as evening primrose oil (EPO), have been shown to have anticancer properties when used alone, their combination with the anticancer medicine tamoxifen (TAM) has yet to be investigated. The present study aimed to investigate the anticancer efficacy of EPO, alone or in combination with TAM, in the BC cell lines MCF-7 and MDA-MB-231, as well as to elucidate the mechanism of action. Methods: The MTT assay was used to investigate the cytotoxic effect of EPO on the two cell lines, and we discovered an acceptable IC₅₀ that was comparable to TAM. The ELISA, qRT-PCR, flow cytometry and colorimetric techniques were used. Results: The combination of EPO and TAM suppressed the VEGF level, VEGF gene expression and Cyclin D1 signaling pathways, arrested the cell cycle, and induced the apoptotic signaling pathways by increasing the Bax/Bcl-2 ratio and caspase 3 activity; this revealed significant anti-tumor activity. Conclusions: The most significant finding of this study was the confirmation of the anticancer activity of the natural product EPO, which potentiated the activity of the anticancer drug TAM against MCF-7 and MDA-MB-231 BC cell lines through the induction of apoptosis, inhibiting angiogenesis and halting cell proliferation.     

Synthesis and in vitro antitumor activity of novel diaryl urea derivatives

A series of novel diaryl ureas containing 4-[（2-amino-6-trifluromethyl）pyrimidine-4-yl]piperazine-l-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib,some compounds showed more potent and a broader spectrum of anti-cancer activities.Among them,compound 2p demonstrated significant inhibitory activities against MDA-MB-231,HT-29 and MCF-7 cell lines with IC₅₀ values of 0.016,0.63,0.001μmol/L, respectively.     

Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.     

Induction of Apoptosis and Regulation of MicroRNA Expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes.     

Antiproliferative Activity of Gold(I) N-Heterocyclic Carbene and Triphenylphosphine Complexes with Ibuprofen Derivatives as Effective Enzyme Inhibitors

A series of gold(I) complexes of ligand ibuprofen-alkynyl (but-3-yn-1-yl 2-(4-isobutylphenyl)propanoate, LE) with N-heterocyclic carbene (LC: 1,3-dimethylimidazol-2-ylidene) and triphenylphosphine (PPh₃) ligands with formula (LE)Au (LC) (complex 1 ) and (LE)Au (PPh₃) (complex 2 ) were synthesized and fully characterized by spectroscopic methods. In order to reveal the cytotoxicity mechanism, the interaction of complex 1 or 2 with cysteine (HCys) has been studied by experimental and density functional theory (DFT) methods. The compounds were investigated for their anticancer activity against MCF-7, MDAMB 231 breast cancer cells, HT-29 colon cancer cells and MCF-10A non-tumor breast cell line. The results were compared with cisplatin and auranofin as reference drugs. The complex 2 showed more cytotoxic activity than complex 1 . The complex 2 was 4.2, 3.7, and 1.7 fold more active than cisplatin against HT-29, MDA-MB-231, MCF-7 cancer cell lines, respectively. The inhibition of thioredoxin reductase of complexes 1 and 2 including cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductase and also the inhibition of glutathione reductase (GR) were studied in detail. Moreover, the cellular uptake and reactive oxygen species (ROS) generation of compounds were investigated. Based on the DFT calculations a relationship between the σ-donor ability of the isolated ligands and cytotoxicity is suggested.     

Rubratoxin C,a new nonadride derivative from an endophytic fungus Penicillium sp. F-14

One new nonadride derivative rubratoxin C （1） together with a known compound rubratoxin B （2） were isolated from an endophytic fungus Penicillium sp. F-14. Their structures were elucidated by various spectroscopic methods. Bioassays showed that 2 had moderate cytotoxic effect against HCT-8, BEL-7402, Ketr3, A2780, MCF-7 and BGC-823 human cancer cell lines, and 1 exhibited weak activity.     

Andrographolide Exhibits Anticancer Activity against Breast Cancer Cells (MCF-7 and MDA-MB-231 Cells) through Suppressing Cell Proliferation and Inducing Cell Apoptosis via Inactivation of ER-α Receptor and PI3K/AKT/mTOR Signaling

Breast cancer is the most common cancer among women worldwide. Chemotherapy followed by endocrine therapy is the standard treatment strategy after surgery or radiotherapy. However, breast cancer is highly resistant to the treatments leading to the recurrence of breast cancer. As a result, the development of alternative medicines derived from natural plants with fewer side effects is being emphasized. Andrographolide isolated from Andrographis paniculata is one of the potential substances with anti-cancer properties in a variety of cell types, including breast cancer cells. This study aims to investigate the anti-cancer effects of andrographolide in breast cancer cells by evaluating cell viability and apoptosis as well as its underlying mechanisms through estrogen receptor (ER)-dependent and PI3K/AKT/mTOR signaling pathways. Cell viability, cell apoptosis, mRNA or miRNA, and protein expression were examined by MTT assay, Annexin V-FITC, qRT-PCR, and Western blot analysis, respectively. MCF-7 and MDA-MB-231 cell viability was reduced in a concentration- and time-dependent manner after andrographolide treatment. Moreover, andrographolide induced cell apoptosis in both MCF-7 and MDA-MB-231 cells by inhibiting Bcl-2 and enhancing Bax expression at both mRNA and protein levels. In MCF-7 cells, the ER-positive breast cancer, andrographolide showed an inhibitory effect on cell proliferation through downregulation of ERα, PI3K, and mTOR expression levels. Andrographolide also inhibited MDA-MB-231 breast cancer cell proliferation via induction of cell apoptosis. However, the inhibition of MCF-7 and MDA-MB-231 cell proliferation of andrographolide treatment did not disrupt miR-21. Our findings showed that andrographolide possesses an anti-estrogenic effect by suppressing cell proliferation in MCF-7 cells. The effects were comparable to those of the anticancer drug fulvestrant in MCF-7 cells. This study provides new insights into the anti-cancer effect of andrographolide on breast cancer and suggests andrographolide as a potential alternative from the natural plant for treating breast cancer types that are resistant to tamoxifen and fulvestrant.     

Effect of meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy on sensitive and multidrug-resistant human breast cancer cells

Meta-tetra(hydroxyphenyl)chlorin (mTHPC) is in clinical trials for the photodynamic therapy (PDT) of localized-stage cancer. The PDT susceptibility of cells expressing multidrug resistance (MDR) phenotype is an attractive possibility to overcome the resistance to cytotoxic drugs observed during cancer chemotherapy. The accumulation, photocytotoxicity and intracellular localization of mTHPC were examined using the doxorubicin selected MCF-7/DXR human breast cancer cells, expressing P-glycoprotein (P-gp), and the wild-type parental cell line, MCF-7. No significant difference in mTHPC accumulation was observed between the two cell lines up to 3 h contact. The photodynamic activity of mTHPC, measured 24 h after irradiation with red laser light (lambda=650 nm), was significantly greater in MCF-7/DXR as compared to MCF-7 cells. A light dose of 2.5 J cm(-2) inducing 50% of cytotoxicity in MCF-7, resulted in 85% cytotoxicity in MCF-7/DXR. The presence of P-gp inhibitors SDZ-PSC-833 and cyclosporin A did not modify the mTHPC-induced cytotoxicity. The difference in intracellular mTHPC distribution pattern between two cell lines may contribute to different photocytotoxicity. Our results indicate that mTHPC mediated PDT could be useful in killing cells expressing MDR phenotype.     

Synthesis of chalcones with anticancer activities

Several chalcones were synthesized and their in vitro cytotoxicity against various human cell lines, including human breast adenocarcinoma cell line MCF-7, human lung adenocarcinoma cell line A549, human prostate cancer cell line PC3, human adenocarcinoma cell line HT-29 (colorectal cancer) and human normal liver cell line WRL-68 was evaluated. Most of the compounds being active cytotoxic agents, four of them with minimal IC?? values were chosen and studied in detail with MCF-7 cells. The compounds 1, 5, 23, and 25 were capable in eliciting apoptosis in MCF-7 cells as shown by multiparameter cytotoxicity assay and caspase-3/7, -8, and -9 activities (p < 0.05). The ROS level showed 1.3-fold increase (p < 0.05) at the low concentrations used and thus it was concluded that the compounds increased the ROS level eventually leading to apoptosis in MCF-7 cells through intrinsic as well as extrinsic pathways.