Arylpropionic acid-derived NSAIDs: New insights on derivatization,anticancer activity and potential mechanism of action

NSAIDs displayed chemopreventive and anticancer effects against several types of cancers. Moreover, combination of NSAIDs with anticancer agents resulted in enhanced anticancer activity. These findings have attracted much attention of researchers working in this field. The 2-arylpropionic acid-derived NSAIDs represent one of the most widely used anti-inflammatory agents. Additionally, they displayed antiproliferative activities against different types of cancer cells. Large volume of research was performed to identify molecular targets responsible for this activity. However, the exact mechanism underlying the anticancer activity of profens is still unclear. In this review article, the anticancer potential, structure activity relationship and synthesis of selected profen derivatives were summarized. This review is focused also on non-COX targets which can mediate the anticancer activity of this derivatives. The data in this review highlighted profens as promising lead compounds in future research to develop potent and safe anticancer agents.     

3-(2'-Bromopropionylamino)-benzamides as novel S-phase arrest agents

We report the synthesis, antiproliferative activity, and SAR of novel 3-(2′-bromopropionylamino)-benzamides. Many of the benzamide compounds showed potent cytotoxicities against Molt-3 leukemia cells. Several compounds exihibited cytotoxicities (under 6.5 μM) against five solid tumor cell lines. The mechanism of action of the most potent benzamide 10l does not involve targeting on tubulin but it causes cell cycle S-phase arrest. This active S-phase arrest agent merits further investigation.     

The C. elegans adult male germline: Stem cells and sexual dimorphism

The hermaphrodite Caenorhabditis elegans germline has become a classic model for stem cell regulation, but the male C. elegans germline has been largely neglected. This work provides a cellular analysis of the adult C. elegans male germline, focusing on its predicted stem cell region in the distal gonad. The goals of this study were two-fold: to establish the C. elegans male germline as a stem cell model and to identify sex-specific traits of potential relevance to the sperm/oocyte decision. Our results support two major conclusions. First, adult males do indeed possess a population of germline stem cells (GSCs) with properties similar to those of hermaphrodite GSCs (lack of cell cycle quiescence and lack of reproducibly oriented divisions). Second, germ cells in the mitotic region, including those most distal within the niche, exhibit sex-specific behaviors (e.g. cell cycle length) and therefore have acquired sexual identity. Previous studies demonstrated that some germ cells are not committed to a sperm or oocyte cell fate, even in adults. We propose that germ cells can acquire sexual identity without being committed to a sperm or oocyte cell fate.     

Metabolism and binding of benzo[a]pyrene in randomly-proliferating,confluent and s-phase human skin fibroblasts

The metabolism of benzo[a]pyrene in randomly proliferating and confluent cultures of human skin fibroblast cells was compared with cell cultures in early S phase of the cell cycle after a G1 block. When each cell population was exposed to [G-³H]benzo[a]pyrene for 24 hours and the organic soluble metabolites in the extracellular medium and intracellular components were analyzed by HPLC, a quantitative increase in metabolism was observed in the confluent cell populations. The amount of organic soluble metabolites in the extracellular medium of the confluent dense cultures was 2.7 times the amount found in randomly proliferating cultures and 1.5 times that of the synchronized cultures. The trans-7,8- and 9,10 dihydrodiols and 3-hydroxy benzo[a]pyrene were the major metabolites formed. Small amounts of the sulphate conjugate, 9-hydroxy-benzo[a]pyrene and the tetrols were also detected. Cytoplasmic as well as nuclear extracts from the confluent cell cultures also contained higher amounts of metabolites compared to those from the randomly proliferating and S-phase cells. The levels of DNA modification by metabolically activated benzo[a]pyrene did not differ among the randomly proliferating, confluent and S-phase cells. However, the S-phase cells exhibited approximately 50-fold increase in the frequency of transformation compared to the randomly proliferating cells. Confluent cells were not transformed by benzo[a]pyrene. These data suggest that factors other than random modification of DNA by the carcinogen might have a significant role in the expression of a transformed phenotype and that metabolism and transformation are not directly related. Furthermore, confluent dense cultures with a heightened capability for metabolism of benzo[a]pyrene were more active in the detoxification of benzo[a]pyrene than in the production of the metabolites associated with cellular transformation.Abbreviations BaP benzo[a]pyrene - BaP-4,5-diol trans-4,5 dihydroxy-4,5-dihydrobenzo[a]pyrene - BaP-7,8-diol trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene - Bap-9,10-diol trans-9,10-dihydroxy-9,10 dihydrobenzo[a]pyrene - CM complete medium - HNF human neonatal foreskin - HPLC high pressure liquid chromatography - PAH polycyclic aromatic hydrocarbon - PDL population doubling - RP randomly proliferating     

DNA ploidy pattern and S-phase characteristics of metastatic melanoma

Samples of 130 metastatic melanomas from 92 patients were analyzed by DNA flow cytometry. DNA aneuploidy was observed in 67% of the patients. DNA indices were evenly distributed from 0.6 to 2.6 Tumors originating from primary lesions in the lower extremities were more frequently DNA aneuploid than those of other sites. S-phase fraction (SPF) was evaluable from 73 tumors. DNA aneuploid tumors had a significantly higher SPF than diploid tumors, and females had a higher SPF than males. Furthermore, distant metastases had a higher SPF than metastases in regional lymph nodes and in transit metastases, probably indicating a higher growth potential in metastases spreading to distant sites.     

The plant cell cycle in context

Biological scientists are eagerly confronting the challenge of understanding the regulatory mechanisms that control the cell division cycle in eukaryotes. New information will have major implications for the treatment of growth-related diseases and cancer in animals. In plants, cell division has a key role in root and shoot growth as well as in the development of vegetative storage organs and reproductive tissues such as flowers and seeds. Many of the strategies for crop improvement, especially those aimed at increasing yield, involve the manipulation of cell division. This review describes, in some detail, the current status of our understanding of the regulation of cell division in eukaryotes and especially in plants. It also features an outline of some preliminary attempts to exploit transgenesis for manipulation of plant cell division.     

Cell cycle dependent distribution of proliferating cell nuclear antigen/cyclin and cdc2-kinase in mouse T-lymphoma cells

The aim of the present study was to investigate bromodeoxyuridine (BrdU) uptake and coordinated distribution of proliferating cell nuclear antigen (PCNA) and p34-cdc2-kinase, two important proteins involved in cell cycle regulation and progression. Flow cytometric analysis of marker proteins in freshly plated mouse T-lymphoma cells (Yac-1 cells), using fluorescein isothiocyanate (FITC)-labeled specific antibodies, showed PCNA distributed throughout the cell cycle with increased intensity in S-phase. PCNA is essential for cells to cycle through S-phase and its synthesis is initiated during late G1-phase before incorporation of BrdU and remains high during active DNA replication. The intensity of PCNA fluorescence increases with the duration of incubation after plating. The cdc2-kinase was detectable in all phases of the cell cycle and the G2-M-phase appears to have the maximum concentrations. The cell cycle analysis of high dose colcemid (2 μg/ml) treated Yac-1 cells showed an aneuploid or hypodiploid population. Although the G2-M-phase seems to be the dominating population in aneuploid cells, the concentrations of cdc2-kinase were variable in this phase of cell cycle. The colcemid treatment at 25 ng/ml arrested 96% of cells in S-phase and G2-M-phase, but PCNA expression was evident in a portion of the cell population in G2-M-phase. Although cells blocked in M-phase seem to have high levels of cdc2-kinase, colcemid renders them inactive. From these data, it appears that the down regulation and/or inactivation of cdc2-kinase could be responsible for the colcemid arrest of cells in M-phase.     

Cytological grading of breast cancer in Giemsa-stained fine needle aspiration smears

A potential cytological nuclear grading based on a semi-quantitative evaluation of three basic nuclear features, size of cell nuclei, anisonucleosis and the proportion of nucleoli-containing-nuclei, was tested on 74 Giemsa-stained fine needle aspiration of breast smears for its reliability in establishing the malignant potential of breast cancer. The prognostic impact of DNA-ploidy and S-phase fraction was also assessed. A good correlation between the three basic nuclear features, DNA-ploidy, S-phase fraction, cytological nuclear grade and histological grade, was shown. Using the cytological nuclear grade proposed, correct classification of cases between low histological grade (HG I) and high histological grade (HG II + HG III) was achieved in 79.73%. A statistically significant difference in 5-year survival rate was also observed between low malignancy grade and high malignancy grade breast cancer patients, regardless of the grading method used. DNA-ploidy and S-phase fraction were not statistically significant in establishing the malignant potential of breast cancer.