montelukast and Prostatic-Neoplasms

Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77-85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (-)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.

Topics: Antigens, Surface; Cell Line, Tumor; Coordination Complexes; Glutamate Carboxypeptidase II; Humans; Male; Microsomes, Liver; Oligopeptides; Prostatic Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Through regulating the expression of hundreds of genes, hypoxia-inducible factor -1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. Here we show that montelukast, a clinical leukotriene receptor antagonist for the treatment of asthma, inhibits hypoxia or CoCl

Topics: Acetates; Cell Line, Tumor; Cell Proliferation; Cyclopropanes; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Prostatic Neoplasms; Protein Biosynthesis; Proteolysis; Quinolines; Receptors, Leukotriene; Sulfides

The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a proinflammmatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinyl LT1 receptor: CysLT1R) expression in prostate cancer (PC), as well as the effects of CysLT1R antagonist on cell proliferation in PC cell lines. CysLT1R expression in PC patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined. CysLT1R expression was detected by immunohistochemistry. Effects of CysLT1R antagonist on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the CysLT1R antagonist induces apoptosis. Initially, only slight CysLT1R expression was detected in BPH and NP tissues and marked CysLT1R expression was detected in PIN and PC tissues. CysLT1R expression was higher in high-grade cancer than in low-grade cancer. Furthermore, CysLT1R antagonist caused marked inhibition of PC cells in a concentration- and time-dependent manner through early apoptosis. In conclusion, CysLT1R is induced in PC, and the results suggest that CysLT1R antagonist may mediate potent anti-proliferative effects of PC cells. Thus, the target of CysLT1R may become a new therapy in the treatment of PC.

Topics: Acetates; Aged; Apoptosis; Cell Proliferation; Cyclopropanes; Disease Progression; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Leukotriene Antagonists; Male; Membrane Proteins; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Quinolines; Receptors, Leukotriene; Sulfides; Tumor Cells, Cultured