Synthesis of a novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones as promising anti-breast cancer agents.

A novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones 4-16 has been designed and synthesized. Preliminary screening of these compounds for their anti-breast cancer activity revealed that compounds 5, 7, and 9 possess the highest anti-cancer activities. The anti-tumor effects of compounds 5, 7, and 9 were evaluated against human breast cancer cell lines (MCF-7 and MDA-MB-231) and human breast cancer cells. They were also evaluated against normal non-cancerous breast cells, isolated from the same patients, to conclude about their use in a potential targeted therapy. Using MTT uptake method, these three compounds 5, 7, and 9 blunt the proliferation of these cancer cells in a dose-dependent manner with an IC50 of 1.27, 1.50 and 1.31 µM respectively. Interestingly, using flow cytometry analysis these three compounds significantly mediated apoptosis of human breast cancer cells without affecting the survival of normal non-cancerous breast cells that were isolated from the same patients. Mechanistically, these compounds blunt the proliferation of MCF-7 breast cancer cells by robustly decreasing the phosphorylation of AKT, mTOR and the expression of VEGF and HIF-1α. Most importantly, compounds 5, 7, and 9 without affecting the phosphorylation and expression of these crucial cellular factors in normal non-cancerous breast cells that were isolated from the same patients. Additionally, using Western blot analysis the three compounds significantly (P < 0.05) decreased the expression of the anti-apoptotic Bcl-2 members (Bcl-2, Bcl-XL and Mcl-1) and increased the expression of the pro-apoptotic Bcl-2 members (Bak, Bax and Bim) in MCF-7, MDA-MB-231 and human breast cancer cells making these breast cancer cells susceptible for apoptosis induction. Taken together, these data provide great evidences for the inhibitory activity of these compounds against breast cancer cells without affecting the normal breast cells.

Enhanced susceptibility to apoptosis and growth arrest of human breast carcinoma cells treated with silica nanoparticles loaded with monohydroxy flavone compounds.

The treatment of drug-resistant cancer is a clinical challenge, hence screening for novel anticancer drugs is critically important. In this study, we investigated the anti-tumor potential of three plant-derived flavone compounds: 3-hydroxy flavone (3-HF), 6-hydroxy flavone (6-HF), and 7-hydroxy flavone (7-HF), either alone or combined with silica nanoparticles (3-HF + NP, 6-HF + NP, and 7-HF + NP), on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of these flavone compounds loaded with NP (flavones + NP) in these cell lines were determined to be 1.5 µg/mL without affecting the viability of normal MCF-10 cells. Additionally, using annexin V - propidium iodide double-staining followed by flow cytometry analysis, we found that the combination of flavones with NP significantly induced apoptosis in MCF-7 and MDA-MB-231 cancer cells. Furthermore, flavones + NP increased the expression of cytochrome c and caspase-9, mediating the growth arrest of these cancer cells. Most importantly, the combination of flavones with NP significantly abolished the expression of ATF-3, which is responsible for the proliferation and invasion of bone-metastatic breast cancer cells. Our data revealed the potential therapeutic effects of these flavones in fighting breast cancer cells, and provide the first insights concerning the underlying molecular mechanisms.

Curcumin analogue 1,5-bis(4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)penta-1,4-dien-3-one mediates growth arrest and apoptosis by targeting the PI3K/AKT/mTOR and PKC-theta signaling pathways in human breast carcinoma cells.

Recent developments in the literature have demonstrated that curcumin exhibit antioxidant properties supporting its anti-inflammatory, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Despite the valuable findings of curcumin against different cancer cells, the clinical use of curcumin in cancer treatment is limited due to its extremely low aqueous solubility and instability, which lead to poor in vivo bioavailability and limited therapeutic effects. We therefore focused in the present study to evaluate the anti-tumor potential of curcumin analogues on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as their effects on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of curcumin analogue J1 in these cancer cell lines were determined to be 5 ng/ml and 10 ng/ml, in MDA-MB-231 and MCF-7 cells respectively. Interestingly, at these concentrations, the J1 did not affect the viability of non-tumorigenic normal breast epithelial cells MCF-10. Furthermore, we found that J1 strongly induced growth arrest of these cancer cells by modulating the mitochondrial membrane potentials without significant effect on normal MCF-10 cells using JC-1 staining and flow cytometry analysis. Using annexin-V/PI double staining assay followed by flow cytometry analysis, we found that J1 robustly enhanced the induction of apoptosis by increasing the activity of caspases in MDA-MB-231 and MCF-7 cancer cells. In addition, treatment of breast cancer cells with J1 revealed that, in contrast to the expression of cyclin B1, this curcumin analogue vigorously decreased the expression of cyclin A, CDK2 and cyclin E and subsequently sensitized tumor cells to cell cycle arrest. Most importantly, the phosphorylation of AKT, mTOR and PKC-theta in J1-treated cancer cells was markedly decreased and hence affecting the survival of these cancer cells. Most interestingly, J1-treated cancer cells exhibited a significant inhibition in the activation of RhoA followed by reduction in actin polymerization and cytoskeletal rearrangement in response to CXCL12. Our data reveal the therapeutic potential of the curcumin analogue J1 and the underlying mechanisms to fight breast cancer cells.

Comparative Protective Effects of N-Acetylcysteine, N-Acetyl Methionine, and N-Acetyl Glucosamine against Paracetamol and Phenacetin Therapeutic Doses-Induced Hepatotoxicity in Rats.

BACKGROUND AND AIMS: Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Paracetamol causes direct hepatic oxidative stress damage. The present study aimed to investigate the possible damaging effects of both PA and PH, when used in therapeutic doses, on rat liver and to compare the antioxidant and hepatoprotective effects of N-acetylcysteine (NAC), N-acetyl-methionine (NAM), and N-acetylglucosamine (NAG) against PA- or PH-induced hepatic damage. METHODS: 90 male Wistar albino rats (120-140 gm) were undertaken, categorized randomly into 9 groups of 10 rats each, and administered by gavage for 2 weeks with DMSO 1% (controls), PA, PA+NAC, PA+NAM, PA+NAG, PH, PH+NAC, PH+NAM, and PH+NAG. Biochemical assays of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), total thiols, and alpha-fetoprotein (AFP) in liver homogenates and serum assays of ALT, AST, 8-hydroxy guanine (8-OH-Gua), and AFP were done. Also histopathological examinations of liver tissues in various groups were done. RESULTS: PA and PH cause significant increase in hepatic levels of MDA, NO, and AFP and serum ALT, AST, and 8-OH-Gua levels, with significant decrease in hepatic GSH and total thiols. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively. CONCLUSIONS: Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH.

Clinical and biochemical study of d-serine metabolism among schizophrenia patients.

BACKGROUND: Schizophrenia is a typical N-methyl-d-aspartate receptor (NMDA-R) hypofunction disorder. Decreased d-serine (d-Ser) levels in the periphery occur in schizophrenia and may reflect decreased availability of d-Ser to activate NMDA-R in the brain. OBJECTIVE: The objective of this study was to investigate the role of d-Ser metabolism in the pathogenesis of schizophrenia via biochemical assays and correlates, the serum level of d-Ser, d-serine racemase (SR) (responsible for its formation from l-serine [l-Ser]) and d-amino acid oxidase (DAAO) (responsible for its catabolism), among different clinical types of schizophrenia patients. PATIENTS AND METHODS: This cross-sectional case-control study was carried out on 100 patients and 50 controls. They were recruited from the outpatients' psychiatric unit of the Neuropsychiatric Department of Assiut University Hospital, Upper Egypt. The type of schizophrenia was determined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), while the severity of schizophrenia was determined according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Serum d-Ser levels were estimated using high-performance liquid chromatography (HPLC), while serum SR and DAAO were measured using commercially available enzyme-linked immunosorbent assay kits. RESULTS: There were significantly lower mean serum levels of d-Ser and SR and significantly higher mean serum levels of DAAO (P-value <0.01 for each) among schizophrenia patients when compared with the control group. Paranoid schizophrenia had the highest frequency, with a significantly lower serum levels of d-Ser and SR in the residual type and significantly higher serum levels of DAAO in undifferentiated and catatonic types. Combined receiver-operating characteristic curve for serum d-Ser, SR and DAAO indicated that the best serum level cutoff points at which schizophrenia manifestations started to appear were ≤ 61.4 mg/L for d-Ser, ≤ 15.5 pg/mL for SR and >35.6 pg/mL for DAAO. CONCLUSION: The present study confirms that disturbed d-Ser metabolism could be implicated in the pathogenesis of schizophrenia.

Voltammetric analysis of drugs.

A review on the voltammetric analysis of drugs is presented. The review includes a summary of the rules that must be considered for drug analysis and a survey of the use of voltammetry for drug analysis in the period from 1998 till 2002.

Simultaneous quantitation of 5- and 7-hydroxyflavone antioxidants and their binding constants with BSA using dual chiral capillary electrophoresis (dCCE) and HPLC with fluorescent detection.

In this article we present two novel uses of the sensitive techniques HPLC fluorescence and dCCE for both the quantitation and binding studies of the 5- and 7-HFs extracted from the plant Alfalfa with Albumin. Ultrasonic extraction method as an extra energy source is used to enhance the extraction efficiency and speed up. The two antioxidants could be easily separated and quantified after a 10.0-min run time. Multiple calibration curves for their analysis exhibited consistent linearity and reproducibility in the range of 0.20-2.00 mg L(-1) for 5-HF (r >0.9979) and 0.01-0.10 mg L(-1) for 7-HF (r >0.9999). Limits of Detection were 0.500 µg L(-1) and 0.025 µg L(-1) for 5-HF and 7-HF respectively. Lower Limits of Quantification were 131.600 µg L(-1) for 5-HF and 6.579 µg L(-1) for 7-HF. Inter-assay imprecision was <10% for both flavones. Mean recovery was 104.76% (range 90%-110%) for 5-HF and 93.18% (range 90%-110%) for 7-HF. Since the intermolecular hydrogen atom transfer in the excited triplet state as well as in the excited singlet state might play an important role in the quenching process of photo-excited molecules in biological systems, the binding constants of these HFs with serum albumin have been also estimated to be 1.910 - 2.019 × 10(5) L mol(-1) and 2.390 - 2.500 × 10(5) L mol(-1) for 5-HF and 7-HF respectively.

Simultaneous separation and determination of Tarabine PFS and Adriblastine using micellar electrokinetic chromatography and high performance liquid chromatography. Application to some biological fluids.

The simultaneous determination of Tarabine PFS and Adriblastine by two independent techniques, viz. micellar electrokinetic chromatography (MEKC) and high performance liquid chromatography (HPLC), has been studied. For MEKC analysis, separations and identifications were accomplished using uncoated fused-silica capillaries and injections were performed in the hydrodynamic mode. The running buffer consisted of 0.05 M borate/phosphate pH 8.70, with 0.10 M SDS at an operating voltage of 15.0 kV and the temperature held at 25.0 degrees C. Under these conditions, the migration times of Tarabine PFS and Adriblastine were 2.70 and 6.40 min, respectively. Calibration curves were established for 0.010-0.300 microg/mL (r = 0.99) Tarabine PFS and 8.000-120.0 microg/mL (r = 0.99) Adriblastine. The limit of detection (LOD) was estimated and found to be 0.003 and 3.000 microg/mL of Tarabine PFS and Adriblastine, respectively. The limit of quantitation (LOQ) was found to be 0.009 and 8.000 microg/mL of Tarabine PFS and Adriblastine, respectively. For HPLC analysis, separations and determinations were performed on teicoplanin stationary phase with reversed mobile phase containing methanol:buffer pH 4.05 (20.0:80.0%, v/v) at 285 nm. Calibration curves were established for 3.000-90.00 microg/mL (r = 0.99) Tarabine PFS and for 10.00-120.0 microg/mL (r = 0.99) Adriblastine. LOD and LOQ were estimated and found to be 0.950 and 2.050 microg/mL of Tarabine PFS and 3.130 and 9.250 microg/mL of Adriblastine, respectively. Both MEKC and HPLC methods were applied for the simultaneous determination of analytes in urine samples. It was found that 8.00-10.0% (Tarabine PFS) and 13.0-15.0% (Adriblastine) of the injected dose was recovered in urine samples with 99.5-102% recovery.