thiourea and Colorectal-Neoplasms

Sirtuin 2 (SIRT2) is a protein lysine deacylase that has been indicated as a therapeutic target for cancer. To further establish the role of SIRT2 in cancers, it is necessary to develop selective and potent inhibitors. Here, we report the facile synthesis of novel lysine-derived thioureas as mechanism-based SIRT2 inhibitors with anticancer activity. Compounds AF8, AF10, and AF12 selectively inhibited SIRT2 with IC

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Lysine; Male; Mice; Mice, Transgenic; Molecular Docking Simulation; Protein Isoforms; Sirtuin 2; Structure-Activity Relationship; Thiourea

Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKβ, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-κB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKβ, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.. Most chemotherapy drugs kill cancer cells by damaging their DNA. The cells have systems to combat this damage and help them to survive, and in some cells these systems work effectively enough to make the cancer effectively resistant to the treatment. For example, a protein called NF-κB can turn on various genes that help to repair damaged DNA. However, DNA is contained the cell nucleus, whereas the inactive form of NF-κB is found outside the cell nucleus. So how does the damaged DNA communicate with – and activate – NF-κB? Previous research had found that another protein called LRP16, which resides in the cell nucleus, plays a crucial role in the repair process that NF-κB is involved in. Li, Wu, An et al. have now studied bowel cancer cells taken from human tissue samples and found that the cancerous cells contained higher levels of LRP16 than cells from the surrounding tissue. Patients with cancers containing very high levels of LRP16 were more severely affected by cancer. Further investigation revealed that when DNA is damaged, LRP16 moves out of the cell nucleus and stabilises how NF-κB interacts with two other proteins; this stabilisation activates NF-κB. LRP16 therefore appears to regulate the signal that travels out of the nucleus from the damaged DNA to activate NF-κB. Further experiments showed that anti-cancer treatments worked best on cancer cells that lacked LRP16. Thus it appears that LRP16 helps cancer cells to respond to and resist the DNA damage caused by chemotherapy. Li, Wu, An et al. went on to identify a drug that prevented the activation of NF-κB by blocking the effects of LRP16. Using this drug alongside chemotherapy drugs made the cells more likely to self-destruct. More work is now needed to develop therapies based on the newly identified drug and to establish how DNA damage activates LRP16.

Topics: Animals; Antineoplastic Agents; Carboxylic Ester Hydrolases; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; DNA; Drug Synergism; eIF-2 Kinase; Enzyme Inhibitors; Etoposide; Heterografts; Humans; I-kappa B Kinase; Isothiocyanates; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; NF-kappa B; Protein Binding; Signal Transduction; Thiourea; Treatment Outcome

Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression.. Immunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells.. The protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells.. The results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4-specific agonist or antagonist in the molecular therapy of CRCs.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclic AMP-Dependent Protein Kinases; Fluorouracil; Gene Expression; Gene Expression Regulation, Neoplastic; Histamine H3 Antagonists; Humans; Imidazoles; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; RNA, Messenger; Signal Transduction; Thiourea