Antiproliferative Activity of N-Acylhydrazone Derivative on Hepatocellular Carcinoma Cells Involves Transcriptional Regulation of Genes Required for G2/M Transition.

Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.

N-acylhydrazone derivative modulates cell cycle regulators promoting mitosis arrest and apoptosis in estrogen positive MCF-7 breast cancer cells.

Breast cancer is the leading cause of cancer death among women worldwide. About 75% of all diagnosed cases are hormone-positive, which are treated with hormone therapy. However, many patients are refractory or become resistant to the drugs used in therapeutic protocols. In this scenario, it is essential to identify new substances with pharmacological potential against breast cancer. VEGFR2 inhibitors are considered promising antitumor agents not only due to their antiangiogenic activity but also by inhibiting the proliferation of tumor cells. Thus, the present study aimed to evaluate the effects of N-acylhydrazone derivative LASSBio-2029 on the proliferative behavior of MCF-7 cells. We observed a promising antitumor potential of this substance due to its ability to modulate critical cell cycle regulators including mitotic kinases (CDK1, AURKA, AURKB, and PLK1) and CDK inhibitor (CDKN1A). Increased frequencies of abnormal mitosis and apoptotic cells were observed in response to treatment. A molecular docking analysis predicts that LASSBio-2029 could bind to the proto-oncoprotein ABL1, which participates in cell cycle control, interacting with other controller proteins and regulating centrosome-associated tubulins. Finally, we created a gene signature with the downregulated genes, whose reduced expression is associated with a higher relapse-free survival probability in breast cancer patients.

Online biological sample preparation with restricted access hybrid carbon nanotubes for determination of anti-smoking drugs.

Untreated samples were injected directly into a column switching system, an online SPE technique, using an extraction column packed with restricted access hybrid carbon nanotubes (RAHCNTs), a novel type of restricted access material, in an ultra-high performance liquid chromatography, coupled to a mass spectrometer (UHPLC-MS/MS). The synthesis of used restricted access material was relatively simple, quick, and reproducible, and had a high material yield. Compared to its predecessor, which is covered with bovine serum albumin (Restricted Access Carbon Nanotubes-RACNTs), RAHCNTs have improved performance when used for the analysis of organic compounds. These molecules have a greater adsorption capacity due to the insertion of hydrophilic monomers (tetraethyl orthosilicate (TEOS), 3-(trimethoxysilyl)propyl methacrylate (MPS), glycerol dimethacrylate (GDMA), and hydroxyethyl methacrylate (HEMA)) in the external layer. In addition, the formation of the hybrid material provides greater chemical and thermal stability, supporting wide pH and temperature ranges, and high concentrations of acidic and basic solutions. It also supports high proportions of organic solvents in the medium. Another significant advantage of the material is its longer lifetime, as it can be reused for approximately 500 analytical cycles without any loss of efficiency, versus 300 for RACNTs. In the method developed to determine anti-smoking drugs (varenicline and bupropion) simultaneously, as well as nicotine and some of their metabolites in human blood serum, the RAHCNTs were capable of retaining the analytes efficiently, whereas the macromolecules were excluded (almost 100%). The method was linear for all the determined analytes (coefficients of determination higher than 0.99), with limits of detection and quantification ranging from 0.6 to 2.5 µg L-1 and from 1.0 to 5.0 µg L-1, respectively. High extraction recovery values were obtained (higher than 88%), as well as inter and intra-assay accuracy and precision results that are in accordance with values recommended by the FDA. The method is promising for therapeutic monitoring and new personalized strategies for patients under antismoking treatment, using a small sample volume (100 µL). In addition, RAHCNTs are capable of simultaneously extracting analytes with very different physical-chemical characteristics.