tosylphenylalanyl-chloromethyl-ketone and Breast-Neoplasms

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Molecular Docking Simulation; NF-kappa B; Peptides; Triazoles

Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-β-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-β-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-α-induced NFκB activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 μM [the concentration to double the activity (CD)=3.8 μM] and its corresponding R-isomer 6f had an IR value of 4.3 (CD=0.2 μM). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NFκB, with the half maximal inhibitory concentration (IC(50)) value of 4.8 μM, and also showed over 60% inhibition at 50 μM of NO production (IC(50)=2.8 μM). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC(50)=14.7 μM). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC(50)=10.5 μM).

Topics: Antineoplastic Agents; Aromatase; Breast Neoplasms; Carbolines; Cell Line, Tumor; Cell Proliferation; Female; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); NF-kappa B; Nitric Oxide; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Transforming growth factor (TGF)-beta signaling makes a significant contribution to the pathogenesis of breast cancer bone metastasis. In other tumor types, TGF-beta has been shown to promote tumor vascularity. Here, we report that inhibition of TGF-beta significantly reduces microvessel density in mammary tumor-induced bone lesions, mediated by decreased expression of both vascular endothelial growth factor (VEGF) and monocyte chemotactic protein (MCP)-1, both known angiogenic factors. Cathepsin G upregulation at the tumor-bone interface has been linked to increased TGF-beta signaling, and we also report that inhibition of Cathepsin G reduced tumor vascularity, as well as VEGF and MCP-1 expression.

Topics: Animals; Antibodies; Bone Neoplasms; Breast Neoplasms; Cathepsin G; Cell Line, Tumor; Chemokine CCL2; Female; Gene Expression Regulation, Neoplastic; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; RNA, Messenger; Serine Proteinase Inhibitors; Signal Transduction; Tosylphenylalanyl Chloromethyl Ketone; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factor A

To examine whether HIV-1 Tat protein increases the metastatic potential of human breast cancer cells through induction of pro-inflammatory tumor microenvironment.. Real-time RT-PCR and ELISA were employed to determine the mRNA and protein expression of IL-6 and IL-8 in highly metastatic human breast cancer cell line, MDA-MB-231. To investigate the transcriptional regulatory mechanisms of Tat-mediated up-regulation of IL-6 and IL-8, EMSA and reporter gene assay were carried out.. Exposure of MDA-MB-231 cells to Tat resulted in a significant and dose-dependent up-regulation of IL-6 and IL-8 mRNA and protein expression. HIV-1 Tat protein also markedly increased NF-kappaB DNA-binding activity and transactivation in MDA-MB-231 cells. Additionally, pretreatment with NF-kappaB inhibitors significantly attenuated the ability of Tat to up-regulate IL-6 and IL-8 expression. It was also found that exposure of MDA-MB-231 cells to Tat induced up-regulation of MMP-9 expression at both mRNA and protein levels.. These results suggest that HIV-1 Tat protein up-regulates expression of IL-6 and IL-8 in human breast cancer cells by NF-kappaB-dependent pathway. These data may contribute to exploration of the new molecular mechanisms leading to novel approaches for the therapeutic drug developments specifically targeted against the inflammatory pathways of breast cancer metastasis in AIDS patients.

Topics: Breast Neoplasms; Cell Line, Tumor; DNA; Gene Products, tat; Humans; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 9; NF-kappa B; Protein Synthesis Inhibitors; Recombinant Proteins; RNA, Messenger; tat Gene Products, Human Immunodeficiency Virus; Tosylphenylalanyl Chloromethyl Ketone; Transcriptional Activation; Up-Regulation