Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine

A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitationThis research was funded by PRIN, Grant 201744BN5T_004S

Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3′,5′-difluoro-3-nitro-[1,1′-biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF-7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4′-fluoro-[1,1′-biphenyl]-4-yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G2- and M-phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G1-phase arrest at low doses (20–40 nm), but did not inhibit in vitro tubulin polymerization

Strong YB-1 expression predicts liver recurrence following resection for colorectal metastases

Introduction The Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein involved in the proliferation and aggressiveness of cancer cells. The aim of this study was to determine whether strong YB-1 expression in neoplastic cells of colorectal liver metastases (CRLM) may have an impact on liver disease-free survival following liver resection. Materials and Methods Immunohistochemistry was performed to evaluate YB-1 in 66 patients who underwent liver resection for CRLM. YB-1 expression was classified as weak (low-staining intensity) and strong (high-staining intensity). Results YB-1 expression was observed in the cytoplasm of all CRLM. YB-1 expression was weak in 17 patients (25.8 %) and strong in 49 patients (74.2 %). Liver recurrence rate was significantly higher in the strong than in the weak expression group: 55.1 vs. 23.5%(p=0.023).Multivariable logistic regression analysis showed that YB-1 strong expression was the only independent risk factor for liver recurrence. The 5-year specific liver disease-free survival rate was 76.0 % in the weak expression group and 41.5 % in the strong expression group (p=0.034). These results were not influenced by clinical prognostic factors of tumor recurrence. Conclusions This is the first study showing that the degree of YB-1 expression in tissue specimens of CRLM predicts liver recurrence following liver resectio