Recombinant anti-human epidermal growth factor receptor type 2 single-chain variable fragment-alpha-luffin fusion protein as a putative immunotoxin against human epidermal growth factor receptor type 2-positive breast cancer cells: an experimental research.

Background: Breast cancer is one of the most frequent causes of cancer death in women. The application of immunotoxins to target overexpressed biomarkers on the surface of cancer cells and delivery of the toxin molecules into these cells has attracted too much attention during the last decade. Objectives: This study was conducted to investigate the possible in-vitro cytotoxic and apoptotic activity of previously designed recombinant immunotoxin compromising anti-HER2 single-chain variable fragment (scFv) and alpha-luffin protein in human epidermal growth factor receptor type 2 (HER2)-positive and HER2-negative breast cancer cell lines. Materials and methods: The previously designed recombinant immunotoxin and alpha-luffin protein were expressed in E. coli host cells and purified using Ni-affinity chromatography. The cytotoxicity of the proteins was tested through MTT and apoptosis studies on HER2-positive and HER2-negative breast cancer cell lines. Results: Treatment of SKBR3 and MDA-MB-468 cells with the immunotoxin caused differential cytotoxicity and apoptotic events. Flow cytometry analysis indicated that the immunotoxin could arrest SKBR3 cells at the G0/G1 phase and induce apoptosis and cell death which were not observed in HER2-negative MDA-MB-468 cells. Annexin V/PI staining revealed late apoptotic events in SKBR3 cells treated with the immunotoxin which was different from the early apoptosis induced by the alpha-luffin protein alone. Conclusions: This immunotoxin could be a promising tool in developing new targeted therapeutic agents against HER2-positive cancer cells. Animal experiments are needed before making firmed conclusions.

Imidazo[1,2-a]quinazolines as novel, potent EGFR-TK inhibitors: Design, synthesis, bioactivity evaluation, and in silico studies.

Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2-a]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o, in particular) had great anti-proliferative activities with IC50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure-activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations.

Thienopyrimidine-based agents bearing diphenylurea: Design, synthesis, and evaluation of antiproliferative and antiangiogenic activity.

An important role has been considered for the vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 µM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

Vitamin D and breast cancer risk: A systematic review and meta-analysis in Iranian patients.

•BsmI and TaqI have association with breast cancer risk in Iranian women.•No significant associations were identified between the FokI and ApaI and breast cancer risk in Iranian women.•No association was detected between Vitamin D level and breast cancer in Iranian women.

Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC50 values between 2.81-29.6 µg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four out of five examined cell lines and was 14 times more selective against MRC5. The flow cytometric analysis confirmed the induction of apoptotic cell death by this compound against HUVEC and MCF-7 cells. In addition, 11n caused sub-G1 phase arrest in the cell cycle arrest. Besides, this compound induced anti-angiogenesis in CAM assay and increased the level of caspase-3 by 5.2 fold. The western-blot analysis of the most active compound, 11n, revealed the inhibition of VEGFR-2 phosphorylation. Molecular docking study also showed the important interactions for compound 11n.

Effects of noncoding RNAs in radiotherapy response in breast cancer: a systematic review.

Radiotherapy has an essential role in breast cancer treatment. However, tumor cells may be resistant to radiotherapy. Noncoding RNAs are considered regulators of different pathways which modulate radiotherapy. This systematic review classifies long noncoding RNAs, and microRNAs precipitated in the radiation response of breast cancer patients. A total of 14 microRNAs and 8 long noncoding RNAs were studied in this review. MiR-22, miR-200 c, Let7, and LINP1 as tumor suppressors increase the effect of radiotherapy in BC. However, some noncoding RNAs such as HOTAIR, NEAT1, and miR-21 are precipitated in radio-resistance breast cancers. Significant changes in the pattern of noncoding RNAs expression before and after radiotherapy make them a good candidate for the prognosis and prediction of radiotherapy response. MiR-21 and miR-182 can promote radio-resistance via cancer stem cells. At last, the molecular mechanisms initiating radio-resistance were also examined to find the candidate noncoding RNAs for the development of radiation-sensitized agents.

Mesenchymal Stem Cells Pretreatment With Stromal-Derived Factor-1 Alpha Augments Cardiac Function and Angiogenesis in Infarcted Myocardium.

BACKGROUND: Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI). METHODS: The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation. RESULTS: SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240MSC, SDF1αMSC, and VEGF-A165MSC in comparison to the control group. CONCLUSIONS: These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.

Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis.

Inhibition of angiogenesis is a promising strategy for the treatment of cancer. Herein, we describe the design and synthesis of thieno[2,3-d]pyrimidine-1,3,4-thiadiazole-aryl urea derivatives 11a-m to evaluate their efficacy in the chick chorioallantoic membrane (CAM) assay. Among target agents, 11i had a considerable activity against prostate cancer cell line, PC3 (IC50 = 3.6 µM). Moreover, induction of apoptosis, good inhibitory activity against the growth of capillary blood vessels, and inhibition of VEGFR-2 phosphorylation were noticeable parameters which convinced us that 11i could be considered as a promising candidate for the discovery of novel drugs to treat tumors, particularly prostate cancer.

Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.

A series of quinazolin-4(3H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC50 = 17.7 µM)which was comparable with sorafenib (IC50 = 17.3 µM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC50 = 6.1 µM). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f, they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y.

Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety.

A series of new coumarin-containing compounds 3a-l and 4a-c was designed and synthesized based on the chalcone-type 4-amino-5-cinnamoylthiazole scaffold 2, and screened for their in vitro anticancer and antioxidant activities. Representatively, the 2-thiomorpholinothiazole derivative 3k with IC50 values of 7.5-16.9 µg/ml demonstrated good cytotoxic effects against tested cell lines MCF-7, HepG2 and SW480. Further investigation by flow cytometric analysis confirmed that this compound induces apoptotic cell death in MCF-7 cells and cause G1-phase arrest in the cell cycle. Moreover, most of compounds had intrinsic potential for radical scavenging activity and ferric-reducing power as investigated by DPPH and FRAP assays.

Synthesis and biological evaluation of 4-amino-5-cinnamoylthiazoles as chalcone-like anticancer agents.

A series of 4-amino-5-cinnamoylthiazoles 3a-p were designed and synthesized as chalcone-like anticancer agents. The synthesized derivatives 3a-p were evaluated for their in vitro antiproliferative activities against three different human cancer cell lines including MCF-7, HepG2 and SW480. Most of compounds could significantly prevent proliferation of tested cell lines. In particular, the pyrrolidine derivative 3e namely (E)-1-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one showed promising activity, especially against HepG2 cells (IC50 = 10.6 µg/ml). Flow cytometric analyses revealed that the prototype compound 3e can prevent the proliferation of HepG2 cells by blockade of the cell cycle at the G2 phase and induction of apoptosis.

Wip1: A candidate phosphatase for cancer diagnosis and treatment.

The critical regulatory mechanisms in numerous cellular pathways including cell survival and DNA damage response mostly depend on phosphorylation and dephosphorylation of proteins. The serine/threonine phosphatase wild-type p53-induced phosphatase 1 (Wip1) is a growth-promoting phosphatase and its numerous downstream targets are important tumor suppressors. Here, we review the Wip1 activity and its relevance to cancer as an oncoprotein. Consecutive investigations about Wip1 and its relation to cancer is critical, as these studies ultimately contribute to the etiology of cancer. A number of innovative studies have recently investigated the importance of Wip1 as a new candidate for cancer diagnosis and prognosis. Accordingly, we discuss the present challenges of using Wip1 as a target for cancer treatment.