Downregulating activated epidermal growth factor receptor has no effect on RBM5 expression.

Background: We were interested in determining how the tumor suppressor gene RBM5 is regulated in lung cancers. Previous studies suggested that the gene expression is related to histological subtype and smoking exposure, since in small cell lung cancers the RBM5 gene is deleted whereas in non-small cell lung carcinomas (NSCLC) RBM5 expression is reduced. Of particular interest was the recent finding that in lung adenocarcinomas, a histological subtype of NSCLC, smoking exposure correlated with mutational activity in the transforming growth factor alpha (TGF-a) signaling pathway.

Quinoline as a privileged scaffold in cancer drug discovery.

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity.

Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells.

Background: Akt/PKB is a promising anticancer therapeutic target, since abnormally elevated Akt activity is directly correlated to tumor development, progression, poor prognosis and resistance to cancer therapies. Currently, the unique role of each Akt isoform and their relevance to human breast cancer are poorly understood.

Methodology/principal Findings: We previously found that Akt1, 2 and 3 are localized at specific subcellular compartments (the cytoplasm, mitochondria and nucleus, respectively), raising the possibility that each isoform may have unique functions and employ different regulation mechanisms.

Design and synthesis of chloroquine analogs with anti-breast cancer property.

A series of chloroquine (CQ) analogs were designed and synthesized in a repositioning approach to develop compounds with high anti-breast cancer property. The compounds were then examined for their antiproliferative effects on two human breast tumor cell lines and a matching non-cancer cell line. Although many of them showed substantial antiproliferative effects on breast cancer cells examined, two compounds, 7-chloro-N-(3-(4-(7-(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)propyl)quinolin-4-amine (14) and {3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-(7-trifluoromethyl-quinolin-4-yl)-amine (26), emerged as the most active among this series.

Smoking (active and passive), N-acetyltransferase 2, and risk of breast cancer.

Background: The relationship between smoking and breast cancer remains controversial. The study aim was to assess the relationship of passive and active smoking to breast cancer risk by N-acetyltransferase 2 (NAT2) phenotype, using a comprehensive assessment of both passive and active smoking.

Methods: We undertook a population-based case-control study in Northeastern Ontario, Canada of 347 women diagnosed (2002-2004) with breast cancer and 775 population-based controls.

Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: a hybrid pharmacophore approach.

A novel class of 4-piperazinylquinoline derivatives based on the isatin scaffold were designed by molecular hybridization approach and synthesized for biological evaluation. Subsequently, the compounds were examined for their cytotoxic effects on two human breast tumor cell lines, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on the breast cancer cell lines examined, the compound 4-bromo-1-[4-(7-chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-1H-indole-2,3-dione (5b) and N(1)-[4-(7-trifluoromethyl-quinolin-4-yl)]-piperazin-1-ylmethyl-4-chloro-1H-indole-2,3-dione-3-thiosemicarbazone (8a) emerged as the most active among this series.

A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells.

The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N'-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethyl-amine hydrochloride).

Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.

Chloroquine (CQ), N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as "Resochin" by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans.

Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity.

A hybrid pharmacophore approach was used to design and synthesize isatin-benzothiazole analogs to examine their anti-breast cancer activity. The cytotoxicity of these compounds were determined using three different human breast tumor cell lines, MDA-MB231, MDA-MB468, MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on all the cancer cell lines examined, the compounds 4-bromo-1-diethylaminomethyl-1H-indole-2,3-dione (2l) and 4-chloro-1-dimethylaminomethyl-3-(6-methyl-benzothiazol-2-ylimino)-1,3-dihydro-indol-2-one (5e) emerged as the most active compounds of this series.

Proliferating cell nuclear antigen: a proteomics view.

Proliferating cell nuclear antigen (PCNA), a cell cycle marker protein, is well known as a DNA sliding clamp for DNA polymerase delta and as an essential component for eukaryotic chromosomal DNA replication and repair. Due to its mobility inside nuclei, PCNA is dynamically presented in a soluble or chromatin-associated form. The heterogeneity and specific modifications of PCNA may reflect its multiple functions and the presence of many binding partners in the cell.

The efficacy and selectivity of tumor cell killing by Akt inhibitors are substantially increased by chloroquine.

This study was to evaluate the enhancement value of chloroquine (CQ) in cancer cell killing when used in combination with Akt inhibitors. The results showed that the combination of CQ and Akt inhibitors is much more effective than either one alone. Importantly, the CQ-mediated chemosensitization of cell killing effects by Akt inhibitors is cancer specific.

RBM6-RBM5 transcription-induced chimeras are differentially expressed in tumours.

Unlabelled: Transcription-induced chimerism, a mechanism involving the transcription and intergenic splicing of two consecutive genes, has recently been estimated to account for approximately 5% of the human transcriptome. Despite this prevalence, the regulation and function of these fused transcripts remains largely uncharacterised.

Results: We identified three novel transcription-induced chimeras resulting from the intergenic splicing of a single RNA transcript incorporating the two neighbouring 3p21.

Characterization of proliferating cell nuclear antigen (PCNA) isoforms in normal and cancer cells: there is no cancer-associated form of PCNA.

In order to clarify the status of PCNA in normal and transformed cells, we performed analysis of this protein by 2D-PAGE, Western blot and mass spectrometry. All the cell lines examined contained the major PCNA form (pI 4.57/30kDa), that is not post-translationally modified.

Synthesis and in vitro cytotoxicity evaluation of 4-aminoquinoline derivatives.

A series of 4-aminoquinoline derivatives were synthesized by the reaction of 4-chloro-7-substituted-quinolines with the corresponding mono/dialkyl amines. The structures of the synthesized compounds were confirmed by NMR and FAB-MS spectral and elemental analyses. Subsequently, the compounds were examined for their cytotoxic effects on two different human breast tumor cell lines: MCF7 and MDA-MB468.

Characterization of the human proliferating cell nuclear antigen physico-chemical properties: aspects of double trimer stability.

Its toroidal structure allows the proliferating cell nuclear antigen (PCNA) to wrap around and move along the DNA fiber, thereby dramatically increasing the processivity of DNA polymerization. PCNA is also involved in the regulation of a wide spectrum of other biological functions, including epigenetic inheritance. We have recently reported that mammalian PCNA forms a double trimer complex, which may be critically important in coordinating DNA replication and other cellular functions.