Human Cell Line MCF-7 Research Articles

Targeting claudin-4 enhances chemosensitivity in breast cancer.

Triple negative breast cancer (TNBC) is characterized by highly aggressive phenotype, limited treatment options and a poor prognosis. In the present study, we examined the therapeutic effect of anti–claudin (CLDN)‐4 extracellular domain antibody, 4D3, on TNBC. When the expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 114 IDC (78 cases from 2004 to 2009 in a single center and 36 cases of tissues array), CLDN1 had lower expression than CLDN4 and was correlated with histological grade. In contrast, expression of CLDN4 was correlated with histological grade, receptor subtype, and stage. CLDN4 expression in human IDC cell lines MCF‐7 (luminal subtype) and MDA‐468 (TNBC) was at the same level. In both cells, paclitaxel (PTX)‐induced growth suppression was enhanced by 4D3. Furthermore, 4D3 increased both intracellular PTX concentration (in both cells) and apoptosis. In the mouse model, 4D3 promoted the antitumor effect of PTX on subcutaneous tumors and reduced lung metastasis. The combination of PTX and 4D3 reduced M2 macrophages and mesenchymal stem cells in the tumor. 4D3 also reduced stemness of the tumors and increased the intratumoral pH. Moreover, concurrent treatment with 4D3, PTX and tamoxifen, or with PTX and tamoxifen in MDA‐468 also showed the same level of antitumor activity and survival as MCF‐7. Furthermore, in a bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Thus, CLDN4 targeting of the antibody facilitated existing therapeutic effects.

Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics.

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 μM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with Ki value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.

Effect of S-Allyl -L-Cysteine on MCF-7 Cell Line 3-Mercaptopyruvate Sulfurtransferase/Sulfane Sulfur System, Viability and Apoptosis.

The S-Allyl-L-cysteine (SAC) component of aged garlic extract (AGE) is proven to have anticancer, antihepatotoxic, neuroprotective and neurotrophic properties. γ-Cystathionase (CTH), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) are involved in H2S/sulfane sulfur endogenous formation from L-cysteine. The aim of the study was to determine the effect of SAC on MCF-7 cells survival and apoptosis, which is a widely known approach to reduce the number of cancer cells. An additional goal of this paper was to investigate the effect of SAC on the activity and expression of enzymes involved in H2S production. The experiments were carried out in the human breast adenocarcinoma cell line MCF-7. Changes in the cell viability were determined by MTT assay. Cell survival was determined by flow cytometry (FC). Changes in enzymes expression were analyzed using Western blot. After 24 h and 48 h incubation with 2245 µM SAC, induction of late apoptosis was observed. A decrease in cell viability was observed with increasing SAC concentration and incubation time. SAC had no significant cytotoxic effect on the MCF-7 cells upon all analyzed concentrations. CTH, MPST and CBS expression were confirmed in non-treated MCF-7 cells. Significant decrease in MPST activity at 2245 µM SAC after 24 h and 48 h incubation vs. 1000 µM SAC was associated with decrease in sulfane sulfur levels. The presented results show promising SAC effects regarding the deterioration of the MCF-7 cells’ condition in reducing their viability through the downregulation of MPST expression and sulfate sulfur level reduction.

Synthesis and characterization of Sm2(MoO4)3, Sm2(MoO4)3/GO and Sm2(MoO4)3/C3N4 nanostructures for improved photocatalytic performance and their anti-cancer the MCF-7 cells

Samarium molybdate nanoparticles (Sm2(MoO4)3) were prepared through a hydrothermal procedure and were used to form various composites with graphene oxide (GO) and carbon nitride (C3N4). The changes in the dimensions and morphology of the products were prepared using template agents like cetyltrimethyl ammonium bromide (CTAB), Sodium dodecyl sulfate (SDS) (≥90%), Triton X-100 (90%), Polyvinyl alcohol (95%), Ethylene glycol (≥99%), and polyvinylpyrrolidone (PVP). DRS analysis indicated band gap for the Sm2(MoO4), Sm2(MoO4)3/GO, and Sm2(MoO4)3/C3N4 as 3.75, 3.15, and 3.4 respectively. The characteristics of the prepared nanostructures were studied through X-ray diffraction (XRD), energy dispersive X-ray (EDX), and scanning electron microscopy (SEM). Finally, the activity of the prepared Sm2(MoO4)3 as photo-catalysts for the degradation of different organic dyes such as methyl orange (MO), methylene blue (MB), and rhodamine B (Rh B) was evaluated. The photocatalytic property of Sm2(MoO4)3/C3N4 and Sm2(MoO4)3/GO for the degradation of MO, was obtained. Based on the empirical data Sm2(MoO4)3/C3N4 had the strongest photodegradation effect as compared to the other compounds tested after around 40 min. BET analysis revealed that the specific surface area of the Sm2(MoO4)3 nanocomposite prepared using C3N4 is 15 times that of in the absence of C3N4. Also, the cytotoxicity of synthesized samples was evaluated using MTT assay against human cell lines MCF-7 (cancer), and its IC50 was about 125 mg/L.

Over-expression of CDX2 alleviates breast cancer by up-regulating microRNA let-7b and inhibiting COL11A1 expression

BackgroundmicroRNA Let-7 serves as a tumor suppressor by targeting various oncogenic pathways in cancer cells. However, the underlying mechanism of its involvement in breast cancer remains largely unknown. With our research, our endeavor is to explore the role of the CDX2/let-7b/COL11A1 axis in breast cancer cell activities.MethodsTumor tissues and adjacent normal tissues were collected from 86 patients with breast cancer. Human breast cancer epithelial cell line MCF-7 was treated with over-expressed CDX2, let-7b mimic, shRNA against COL11A1 and their negative controls. The expression of CDX2, let-7b, and COL11A1 in the tissues and cells was determined by RT-qPCR. Interactions among CDX2, let-7b, and COL11A1 were detected by ChIP and dual-luciferase reporter assay, respectively. After different transfections, cell invasion, migration, and proliferation abilities were determined by Transwell and EdU assays. Lastly, tumor xenografts in nude mice were established and hematoxylin and eosin staining was performed to assess the tumor growth and lymph node metastasis.ResultsCDX2 and let-7b were poorly expressed in breast cancer cells and tissues. CDX2 bound to let-7b and promoted the expression of let-7b, which contrarily inhibited the expression of COL11A1. Cancer cell proliferation, invasion, migration, and metastasis were stimulated when CDX2 and let-7b were depleted or COL11A1 was over-expressed. Xenograft tumors growth and metastasis were in accordance with the results of cellular experiments.ConclusionIn agreement with these observations, we could reach a conclusion that CDX2 could promote let-7b expression, which may exert an inhibitory effect on the proliferation, migration, and metastasis of breast cancer cells via repressing the expression of COL11A1, providing a novel therapeutic strategy for the treatment of metastatic breast cancer.

Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers Through an Intrinsic Apoptosis Pathway.

In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; up regulation of Apaf-1, Bax, and cytochrome c; down regulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner.

Processed Fruiting Bodies of Lentinus edodes as a Source of Biologically Active Polysaccharides

Water soluble polysaccharides (WSP) were isolated from Lentinus edodes fruiting bodies. The mushrooms were previously subjected to various processing techniques which included blanching, boiling, and fermenting with lactic acid bacteria. Therefore, the impact of processing on the content and biological activities of WSP was established. Non-processed fruiting bodies contained 10.70 ± 0.09 mg/g fw. Boiling caused ~12% decrease in the amount of WSP, while blanched and fermented mushrooms showed ~6% decline. Fourier transform infrared spectroscopy analysis (FTIR) confirmed the presence of β-glycosidic links, whereas due to size exclusion chromatography 216 kDa and 11 kDa molecules were detected. WSP exhibited antioxidant potential in FRAP (ferric ion reducing antioxidant power) and ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assays. Cytotoxic properties were determined on MCF-7 and T47D human breast cell lines using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. Both biological activities decreased as the result of boiling and fermenting.

Extraction and chemical characterization of novel water-soluble polysaccharides from two palm species and their antioxidant and antitumor activities

ABSTRACT Two crude heteropolysaccharides were isolated from fruits of Caryota mitis and Chamaerops humilis in percentages of 2.65 and 3.89, respectively. In the case of Caryota mitis (CM) polysaccharide, it consisted of galactose, glucose and mannose as the predominant monosaccharides. While mannose, galactose and arabinose were respectively the predominant monosaccharides in the structure of Chamaerops humilis (CH) crude polysaccharide. Sixteen common amino acids were recognized to be components of the protein-bound polysaccharides of CM and CH. The major amino acid in CM and CH polysaccharides was tyrosine (1.091ng/g) and arginine (0.684 ng/g), respectively. Antioxidant activities of tested polysaccharides were examined by measuring its scavenging ability on 2,2-diphenyl-1-picrylhydrazyl and ferric reducing activity power assay. In a concentration of 1 mg/ml, CM and CH polysaccharides recorded FRAP values of 0.56 and 0.44 µmol Fe++/g, respectively. The scavenging activity of CM sample was higher (IC50, 422.11 µg/ml) than that of CH polysaccharide (IC50, 630.0 µg/ml). Also, the antitumor activity of CM and CH polysaccharides was investigated using HepG2 and MCF-7 human cell lines. The polysaccharide of Caryota mitis had a higher antitumor activity than that of CHPs; it had IC50 values of 13.6 and 46.4 µg/ml in HepG2 and MCF-7 assays, respectively.

One-pot biosynthesis of CdS quantum dots through in vitro regeneration of hairy roots of Rhaphanus sativus L. And their apoptosis effect on MCF-7 and AGS cancerous human cell lines

Development of green based synthesis of nanoparticles has been regarded as a novel and safe alternative method compared to conventional methods. Semiconductor cadmium sulfide quantum dots (CdS QDs) possess unique biological and medical applications includes labeling cells, diagnosing of diseases and imaging intercellular events. The present paper reports the biosynthesis of CdS QDs through aqueous extracts of the regenerated hairy roots of Rhaphanus sativus L. as the organic source for both reducing and stabilizing of Cd and S precursor ions. The characterization of synthesized QDs showed maximum absorbance peak of 460 nm and fluorescence spectrum of cadmium sulfide at 530 nm. The results of Transmission Electron Microscope (TEM) and EDS analysis demonstrated that the particles were morphologically spherical with size distribution between 2–7 nm and confirmed presence of CdS QDs. Fourier transform infrared spectroscopy (FT-IR) also showed the active presence of aromatic, amino, and carboxyl groups on the surface of quantum dots. Cytotoxicity effect of the synthesized CdS QDs on two cell lines include MCF-7 breast cancer and AGS gastric cancer were assayed through MTT assay. The results showed significant inhibitory effects of synthesized QDs on treated cells in a dose dependent manner. It was also concluded that CdS QDs had more apoptosis effect on MCF-7 cells rather than AGS cell lines. The obtained results clearly illustrated that the synthesis of CdS quantum dots with standard features would be possible through cost-effective, reliable, environmentally friendly and less toxic alternative method compared to chemical and physical processes and the MTT toxicity assay also illustrated the significant apoptotic effects of synthesized CdS QDs on carcinogenesis.

Synthesis and Biological Evaluation of Novel Triazolyl-Acridine Derivatives as Cytotoxic Agents

Novel triazolyl-acridine compounds were synthesized in 4 series of 9-(2-(substituted phenyl-1H-1,2,3-triazol-1-yl)ethoxy)acridine, 9-(3-(4-(2-substituted phenyl)-1H-1,2,3-triazol-1-yl)propoxy) acridine, N-(2-(4 substituted phenyl-1H-1,2,3-triazol-1-yl)ethyl)acridin-9-amine and N-(3-(4-(substituted phenyl)-1H-1,2,3-triazol-1-yl)propyl)acridin-9-amine using appropriate synthetic procedures and screened for cytotoxic activity. The structures of all synthesized compounds were confirmed by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance and mass spectroscopy and these compounds were assayed in vitro for cytotoxic activity against MCF-7 (human breast adenocarcinoma cell line) and HT-29 (human colon adenocarcinoma cell line) cells. Tested compounds showed better cytotoxic activities in terms of IC50 value against MCF-7 and HT-29 cells. Methyl substituted compound MPP-9 exhibited excellent sensitivity with IC50 value 1 and 2 µM, against MCF-7 and HT-29, respectively. Unsubstituted MPP-1 and chloro-substituted MPP-2 and MPP-5 also exhibited good IC50 value ranges from 2-4 µM against both cell lines. These compounds were active at micro molar concentrations. Data study revealed that synthesized compounds are promising leads for future as cytotoxic agents.

One Pot Synthesis of Schiff Base Complexes of Cu(II), Zn(II), Ni(II), Co(II) and their Cytotoxicity, Molecular Docking and Antibacterial Activity

A novel Schiff base ligand (L), N(4)-cyclohexyl-2-(1-(5-chlorothiophen-2-yl)ethylidene)hydrazine carbothioamide was synthesized from isothiocyanatocyclohexane and hydrazine. All the synthesized transition metal(II) complexes were characterized by functional peak using 1H NMR, 13C NMR, FT-IR, UV-vis spectroscopy and metal complex atomic ratio of complexes of thiosemicarbazones were characterized by elemental analysis. Schiff base and its metal(II) complexes were screened in vitro medicinal drug activity against Gram positive and Gram-negative microorganisms and anti-cancer activity against human carcinoma cell line MCF-7 was detected with nickel(II) and cobalt(II) complexes. Further, the cytotoxity of ligand and its metal(II) complexes were tested on a Monkeys normal cell line and found to be non-toxic (< 200 μg/mL). In the present work, the molecular mechanism of anticancer (breast cancer) activity of the compounds were also disscussed.

Synthesis and characterization of microbial poly3-hydroxybutyric acid nanocarrier for curcumin as an antibreast cancer agent

Background and objective In a previous study, the authors produced, optimized, characterized, and purified the poly3-hydroxybutyric acid (PHB) using the locally isolated Bacillus flexus bacterial strain. The development of a biodegradable drug carrier as an efficient delivery system has received great interest over the past few decades. The objective of this study was to produce a nano-PHB carrier for curcumin to be more effective in tumor fighting. Materials and methods PHB was produced on the optimized medium by B. flexus strain. The nano-PHB form was produced using the nanoprecipitation technique. The size, shape, and characteristics of loaded curcumin nano-PHB particles were performed using zeta-potential, scanning electron microscopy, and Fourier transform infrared spectroscopy techniques. The antitumor effect of the nano-PHB loaded curcumin was performed using human breast adenocarcinoma MCF-7 cell line. Results and conclusion In this study, a naturally developed, biodegradable, and biocompatible nanosized carrier for curcumin-targeted delivery in breast-cancer cells with higher encapsulation efficiency (95.5%) was formulated. The size range of both free PHB and curcumin-loaded PHB was 237 and 260 nm respectively. The nanoparticles exhibited a spherical shape with no aggregation which is confirmed by electron microscopy, indicating a higher colloidal stability. The curcumin-loaded PHB nanocarrier showed a sustained drug release behavior. In-vitro anticancer assays showed the superiority of curcumin-loaded PHB nanocarrier over free curcumin for fighting breast cancer. These results show that the PHB biopolymer acts as an efficient carrier vehicle for the curcumin.

Combining RANK/RANKL and ERBB-2 targeting as a novel strategy in ERBB-2-positive breast carcinomas

BackgroundERBB-2 is overexpressed in about 20% of breast cancers (BCs), indicating poor prognosis. The receptor activator of nuclear factor-κB (RANK) pathway is implicated in ERBB-2 (+) BC. The purpose of this study was to elucidate the underlying molecular mechanism of this interaction and the beneficial impact of dual targeting of RANK and ERBB-2 pathways.MethodsWe used SKBR3, MCF7, MDA-MB-453, and BT-474 human BC cell lines. We examined RANK and RANKL expression using RT-PCR, Western blot, and immunofluorescence. The evaluation of RANK expression in a cohort of BC patients was performed using immunohistochemistry. The interaction between RANK and ERBB family members was detected using proximity ligation assay (PLA), which enables the visualization of interacting proteins. We used inhibitors of both pathways [trastuzumab (T), pertuzumab (P), denosumab (D)]. NF-κB pathway activation was studied using Western blot. Cell growth and viability was evaluated using XTT, flow cytometry, and clonogenic assay. For cell migration evaluation, scratch assay was performed. Data were analyzed by one-way ANOVA.ResultsCell lines express RANK and RANKL. RANK immunostaining was also detected in human BC tissue samples. RANK receptor dimerizes with ERBB family members. RANK/ERBB-2 dimer number seems to be associated with ERBB-2 expression (SKBR3, 5.4; BT-474, 8.2; MCF7, 0.7; MDA-MB-453, 0.3). RANK/ERBB-2 dimers were decreased in the presence of the inhibitors D, T, and P, while they were increased after RANKL (R) treatment in SKBR3 (m, 5.4; D, 1.2; T, 1.9; DT, 0.6; TP, 1; DTP, 0.4; R, 11.8) and BT-474 (m, 8.2; D, 3.1; T, 4.3; DT, 0.7; TP, 3.4; DTP, 3.2; R, 11.6). Combination targeting of SKBR3 further decreased NF-κB pathway activation compared to single targeting. In SKBR3, RANKL and ERBB-2 blockage resulted in reduced cell proliferation, increased apoptosis, and lower metastatic potential compared to mock cells (m) and reversed values in RANKL presence. The combination treatment of SKBR3 with D, T, and P had an advantage in functional traits compared to single targeting. Denosumab suppressed NF-κB signaling and diminished proliferation rate in MDA-MB-453 cells. MCF7 did not correspond to inhibitors.ConclusionsThe results indicate a novel physical and molecular association between ERBB-2 and RANK pathways that affects ERBB-2 (+) BC growth. We also present data suggesting that the combination of anti-ERBB-2 agents and RANKL inhibitors have a potential direct anti-tumor effect and should be further tested in certain BC patients.

Potential in-vitro anti-breast cancer activity of green-synthesized silver nanoparticles preparation against human MCF-7 cell-lines

An efficient bio-catalyzed synthesis of silver nanoparticles from aqueous silver nitrate solution was carried out utilizing the fresh Buchanania axillaris leaves’ aqueous-n-butanolic extract. The high-density yield silver nanoparticles were characterized by UV-Vis (Ultraviolet-visible), Fourier-transform infra-red (FT-IR), X-ray diffraction (XRD), energy dispersive-absorption X-rays (EDX), size and zeta potential analyses. The spherical morphology was confirmed by the scanning electron microscopy (SEM) of the purified product’s sample. The UV-Vis absorption λmax was observed at 419 nm while the IR absorption bands showed up at 3435, 2923, 2852, 1629, 1384, 1056, and 616 cm−1 for the capped nanosilver product. The particle sizes ranged approximately between 17–80 nm. The XRD and EDX spectroscopies confirmed the silver’s elemental composition. The biosynthesized silver nanoparticles showed significant cytotoxicity at a minimum dose of 10 μg ml−1, and an IC50 value of 31.2 μg ml−1 was established in the MTT assays when tested against human breast cancer cell-lines, MCF-7. The cytotoxicities were examined at different concentrations (10 to 100 μg ml−1) as compared to the controls, and the percent inhibitions of the cells’ growths were found increased with increasing concentrations of the silver nanoparticles. Also, the viability of the cells decreased with the increasing concentrations of the silver nanoparticles while the morphological examinations of the MCF-7 cancer cells showed distinguishable alterations in the morphology. Significant cell density changes were also observed confirming the anti-cancer action of the synthesized silver nanoparticles.

Synthesis, characterization and in vitro evaluation of anticancer activity of a new water-soluble thiosemicarbazone ligand and its complexes

A new water-soluble thiosemicarbazone ligand, 4-hydroxyl-3-({[(methylamino)carbonothioyl] hydrazono}methyl)benzoic acid (H3LCOOH) and its complexes with Cu(II), Ni(II), Zn(II), Fe(III) and Mn(III) were synthesized and characterized. These compounds were characterized by conductivity, magnetic susceptibility, elemental analysis, FT-IR, 1H NMR, 13C NMR, and UV–Vis spectroscopy. All the compounds have sufficient solubility and stability in water as a safe, green, and biologic solvent. The compounds were evaluated for their anticancer activities against the human chronic myelogenous K562 leukemia and human breast carcinoma MCF-7 cell lines. All the complexes significantly showed more anticancer activity than the ligand alone and the Cu(II) complex showed considerable cytotoxicity against the tested cell lines. The mechanism of action of the most potent complex, Cu(HLCOO) against K562 cell line was further explored by fluorescence microscopy, flow cytometry, cell cycle and reactive oxygen species (ROS) assays. Hoechst staining and flow cytometry indicated the apoptosis induction ability of Cu(HLCOO) on K562 cells. Mechanistic studies indicated that Cu(HLCOO) complex caused cell cycle arrest at G0/G1 phase and this complex was able to inhibit the cell cycle in a time-dependent manner. Cu(HLCOO) can also increase the reactive oxygen species levels in the K562 cells. The obtained results suggest that the studied compounds can be helpful candidates for further evaluations as chemotherapeutic agents in the treatment of cancer.

Convenient Synthesis and Anticancer Activity of Methyl 2-[3-(3-Phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and N-Alkyl 3-((3-Phenyl-quinoxalin-2-yl)sulfanyl)propanamides.

A series of methyl 2-[3-(3-phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and their corresponding hydrazides and N-alkyl 3-((3-phenylquinoxalin-2-yl)sulfanyl)propanamides were prepared on the basis of the chemoselective Michael reaction of acrylic acid with the parent substrate 3-phenylquinoxaline-2(1H)-thione. The parent thione was produced by a convenient novel thiation method from the corresponding 3-phenylquinoxalin-2(1H)-one. The chemical structures of the newly synthesized compounds were confirmed by elemental analyses, 1H and 13C NMR. The antiproliferative activity of the synthesized compounds was tested against human HCT-116 and MCF-7 cell lines. Out of 25 screened derivatives, 10 active compounds exhibited IC50’s in the range 1.9–7.52 μg/mL on the HCT-116, and 17 active compounds exhibited IC50’s in the range 2.3–6.62 μg/mL on the MCF-7 cell lines compared to the reference drug doxorubicin (IC50 3.23 μg/mL). The structure–activity relationship of the tested compounds was studied through their binding affinity to the human thymidylate synthase allosteric site in silico using molecular docking and proved the quinoxaline ring as a suitable scaffold carrying a peptidomimetic side chain in position 3.

Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

Effects of hydroxyl radicals produced by a zinc phthalocyanine photosensitizer on tumor DNA

Photodynamic therapy (PDT) is a new therapeutic approach for cancer treatment. Its mechanism relies on three elements: photosensitizer, light and oxygen. Under aerobic conditions, a suitable wavelength of light activates the photosensitizer that results in the formation of reactive oxygen species (ROS). We herein report that PDT with a zinc phthalocyanine (ZnPc) photosensitizer coupled with 2,4,6-tris (N, N-dimethylaminomethyl) phenoxy (TAP), termed as ZnPc(TAP)4, has the ability to photodegrade DNA in tumor cells via hydroxyl radicals produced under the red light irradiation, resulting in effective elimination of tumor cells. Furthermore, the high-efficient anti-tumor effect of ZnPc(TAP)4 was verified in a human breast adenocarcinoma cell line MCF-7 tumor-bearing animal model. To the best of our knowledge, this is the first time that destructive effects of hydroxyl radicals produced by PDT on DNA of tumor cells has been documented, which may open up new avenues of antitumor therapy on eliminating the DNA of tumor cells.

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell–selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ± 0.66 μM and 4.71 ± 0.84 μM, respectively when compared with erlotinib (IC50 = 0.05 ± 0.01 μM). Besides, compound 3f also inhibited HER2 notably with an IC50 value of 2.28 ± 0.53 μM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

RNAi silenced NUP88 gene suppresses growth and invasiveness of human breast cancer cell line MCF-7

RNAi silenced NUP88 gene suppresses growth and invasiveness of human breast cancer cell line MCF-7