Substituted aromatic amines were diazotized followed by coupling with malononitrile to afford substituted phenyl hydrazono-malononitrile compounds 2a-c. Compounds 3a-c were prepared through the reaction of substituted phenyl hydrazono-malononitriles 2a-c with phenyl hydrazine, while the reaction of compounds 2a-c with hydrazine hydrate afforded diamino compounds 4a-c. The diamino compounds 4a-c was condensed with different substituted aromatic aldehydes to yield N-benzylidine pyrazole diamines 5a-i. The structure of the newly synthesized compounds was confirmed by IR, 1H NMR, MS spectral data and elemental analysis. Twelve novel compounds 3a-c and 5a-i were screened for their anticancer activities against breast carcinoma (T47D) and human hepatocarcinoma cell lines (Huh- 7) compared with Doxorubicin. The detailed synthesis, spectroscopic data and anticancer activities of the synthesized compounds were reported.
Indoles are aromatic heterocyclic organic compound and became the precursor to many pharmaceuticals. Indoles are found naturally in cruciferous plants and indole derivatives, indole-3-carbinole (I3C) and 3, 3’-diindolylmethane (DIM) can also be synthesized by a variety of methods. In vitro studies indicated that I3C and DIM inhibit cell proliferation, caused cell cycle arrest at G1 phase and induced apoptosis. The precise molecular mechanisms by which indole derivatives exert their tumor suppressive effects in human cancer cells are still unclear. It was reported that indoles alter estrogen metabolism. Microarray gene expression profiling and other studies indicated that indoles regulate many genes that are important for the control of cell cycle, cell proliferation, apoptosis, signal transduction, angiogenesis and cell invasion. In addition, it was found that indoles prevent tumor formation of breast and prostate cancer in animal models. Furthermore, these derivatives were evaluated in human clinical trials phase I and phase II as a potential chemopreventive agents against human breast, ovary, and vulvar intraepithelial neoplasia and colon cancers. Preliminary findings of these studies showed a significant clinical improvement. Interestingly, the use of indole derivatives was found to be safe without any indicated side effects. In conclusion, the results provide an evidence of the benefit of indole-derivatives in the prevention and treatment of hormone-dependent and hormone-independent human cancer. Further clinical trials are needed in order to approve the efficacy of indole derivatives in treatment of human cancer and to evaluate the indole use by the Food and Drug Administration (FDA).
Mahmood Nazari, Mohammad Reza Hajizadeh, Abrahim Eftekhar, Shirin Fattahpour, Hassan Ziaaddini, Gholamhossein Hassanshahi, Mehdi Mahmoodiand Mohsen Rezaeian
Aim and objectives: Diabetes is a metabolic disorder with hyperglycemia due to defects in insulin secretion and function. Several studies investigated the both effects of traditional herbal medicine in diabetes treatment. Therefore, the aim of the present study was to investigate the effects of Morus Alba leaf Extracts (MAE) on hepatic enzyme activity in normal and streptozotocin-induced diabetic rats.
Methods: Forty healthy adult male Wistar rats weighing 250 ± 10 gr were taken for this experiment. Rats were divided into 4 groups (10 rats in each group). Animals treated by a gavage tube for a period of two months as follow: group I: non diabetic control rats which only received distilled water; group II: non-diabetic rats that received (MAE) 1.0 g/kg per day; group III: diabetic control rats treated with distilled water and group IV: Diabetic rats which received MAE 1.0 g/kg per day. At the end of the 8th week, blood samples were collected and serum levels of enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and total bilirubin were measured in all study groups using commercial assay kits. The activity of two antioxidant enzymes including glutathione peroxidase (GPX) and glutathione reductase (GR) were also measured.
Results: Findings of present study demonstrated that MAE significantly decreased serum levels of liver enzymes ALT, AST and ALP in diabetic rats in compare to the diabetic control groups while it increased GPX and GR activity(P<0.05). These results also indicated that MAE did not significantly affect LDH activity in diabetic rats treated with MAE in compared to the diabetic control groups.
Conclusions: According to the present findings it could possibility be suggested that the anti-hyperglycemic effect of MAE is mediated at least partially by increasing liver GPX and GR activity as well as decrease serum levels of liver enzymes ALT, AST and ALP. These results are the other definite evidence supporting MA as traditional medicine for diabetic patients.
Chemotherapy is still the first-line treatment of cancer, even if drugs currently used in therapy generally possess high toxicity and poor selectivity. In the last two decades several efforts have been made to overcome these drawbacks by specifically carrying anticancer drugs to the tumors. Among the different approaches, the so called vitaminmediated drug targeting has recently emerged as a novel and valuable strategy. Indeed, the linkage of cytotoxic drugs to selected vitamins, leading to vitamin-drug conjugates, would result in specifically delivering great amounts of the targeted drug at high doses to cancer cells. Among vitamins, biotin seems to be the most promising targeting agent. The aim of this review is to get an overview on recent success in the conjugation of biotin with molecules endowed with anticancer properties.
Objective: In ovarian cancer, activation of the epidermal growth factor receptor (EGFR) is associated with poor prognosis. The presence of EGFR activators in patient ascites fluid may cause constitutive EGFR activation thereby contributing to metastasis and/or resistance to therapy. Our goal was to identify alterations resulting from constitutive EGFR activation that influence cell behavior and drug sensitivity.
Methods: We used an in vitro model (OVCA 433 cells) to evaluate changes in mesenchymal marker levels and multicellular aggregate (MCA) formation following long term epidermal growth factor (EGF) treatment. We determined sensitivity to cisplatin following EGF treatment and evaluated the role of the mesenchymal marker, N-cadherin, in aggregate formation and sensitivity using siRNA.
Results: We found that EGFR activation led to phenotypic and functional changes in ovarian tumor cells that were retained after ligand was withdrawn (removal). Expression levels of the mesenchymal markers N-cadherin and vimentin were elevated in EGF treated and removal cells. This persistent increase in mesenchymal markers was associated with a significant increase in (MCA) compaction and cell spreading when MCAs were plated on collagen. N-cadherin silencing decreased MCA compaction and spreading in cells following extended exposure to EGF or in cells with high endogenous levels of N-cadherin. Furthermore, the compact MCA structure in EGF treated cells with increased N-cadherin expression conferred resistance to cisplatin and N-cadherin silencing largely restored cisplatin sensitivity.
Conclusion: Our results indicate that prolonged EGFR activation causes a persistent change in mesenchymal marker expression, which regulates compaction and drug sensitivity. The findings implicate N-cadherin as a key regulator of the EGFR-dependent functional changes in MCAs such as compaction, spreading and sensitivity to platinum-based chemotherapeutics. These findings suggest a mechanism by which persistent EGFR activation in the microenvironment may drive changes in ovarian cancer cells that contribute to the poor prognosis associated with EGFR activation.
Urological cancers are among the commonest cancers in western countries. Progress in the domain of prevention and early detection of cancer is well known by researchers but studies have shown that advices for patients are sparse, inconsistent and even contradictory. The possible beneficial effects for prevention and early detection of urologic cancers are addressed in this mini-review. Emphasis will be placed on the role of alcohol and tobacco use, natural compounds, dietary supplements, early detection and pharmacological therapy on the risk of each urologic cancer. Most evidence suggests that alcoholic beverages contain a variety of carcinogenic contaminants that are introduced during fermentation and production. Many chemicals are present in tobacco smoke, including at least 69 known carcinogens. Smokeless tobacco, chewing tobacco and dipping snuff contains at least 28 carcinogens. Calorie restricted diet is associated with improvement of urologic cancer outcomes. Obesity is an established risk factor for kidney and prostate cancer. There is an association between obesity and cancer-specific mortality in bladder cancer. There is limited evidence indicating no association between physical activity and testicular or bladder cancers but a growing body of research suggests a modest risk reduction for kidney cancer and advanced prostate cancer. It seems to be no effect of lycopen and carbohydrates with prostate cancer chemoprevention. In addition, there is little evidence to support daily use of multivitamins to protect against urologic cancers. The tremendous potential benefits of catechins in tea, pomegranate, luteolin and flavanoid, needs further studies to confirm their role in urologic cancers chemoprevention. For medical agents, statins and 5 alpha reductases inhibitors are good candidates for future studies. Screening is not recommended for all urologic cancers except for prostate cancer where controversies remain. In contrast, opportunistic screening leads to early detection and decrease specific cancer mortality for almost all urologic cancers.
A post-cell-removal surface morphology (PCRSM) profiling technique was used to identify the effects of targeted anticancer medicines on cancer cells. Living non-small lung cancer cells, A549 and H1299, were cultivated on a 3-aminopropyltriethoxysilane (γ-APTES) coated silicon wafer surface with and without targeted anticancer medicine added in the culture medium. Atomic force microscopy (AFM) was used to examine the surface morphology profile on the γ-APTES wafer surface after removing the cells. Two different targeted anticancer medicines, epidermal growth factor receptor (EGFR)-inhibitor Iressa (gefitinib) and protein kinase c (PKC)-inhibitor Staurosporine were examined. Our experimental results show that only the cancer cells treated with Staurosporine can have the PCRSM profiles resemble to those of normal cells, whereas those treated with Iressa reserve the PCRSM profiles of the pre-medicine treated cancer cells. This observation indicates that the PCRSM technique is able to detect the cell-traction force difference caused by EGFR-inhibitor and PKC-inhibitor, respectively and Staurosporine is more effective than Iressa in deactivating the cell-substrate interaction of the cancer cells.
Haiming Ding, Bruce Casto, Ye Deng, Kevin Grill, Wenrui Duan, Ning Zhang, Sara Cole, Krista MD La Perle, Xueliang Pan, Douglas Kinghorn A and Steven MD'Ambrosio
Background/Aim: Our studies have shown that an avocado extract (D003) selectively inhibits proliferation in premalignant and malignant but not normal primary human oral epithelial cell lines via an ROS-mediated mechanism. Herein, the in vivo anticancer effect of D003 extract and freeze-dried avocado (FA) was determined in the DMBAinitiated hamster cheek pouch (HCP) model.
Materials and Methods: Tumors were initiated in hamster oral mucosa with DMBA followed by topical application of D003, FA, or vehicle. Tumor lesions were counted and evaluated histologically, epithelial proliferation was investigated using MTT assays, and ROS levels in HCP were examined using two photon microscopy.
Results: D003 significantly inhibited tumorigenesis (tumor number and volume) compared to FA and vehicle, but neither D003 nor FA reversed premalignant changes induced by DMBA. ROS levels that were increased in the mucosa by DMBA treatment were enhanced by D003. D003 significantly reduced proliferation of cells in DMBAinitiated mucosa.
Conclusion: Human cell culture and HCP data show that the phytochemicals extracted from avocado exhibit anticancer activity by inhibiting cancer cell proliferation and progression.