3-Chloro-N′-(2-hydroxybenzylidene) benzohydrazide: An LSD1-Selective Inhibitor and Iron-Chelating Agent for Anticancer Therapy

Abstract

Despite the discovery and development of novel therapies, cancer is still a leading cause of death worldwide. In order to grow, tumor cells require large quantities of nutrients involved in metabolic processes, and an increase in iron levels is known to contribute to cancer proliferation. Iron plays an important role in the active site of a number of proteins involved in energy metabolism, DNA synthesis and repair, such as ribonucleotide reductase, which induce G0/S phase arrest and exert a marked antineoplastic effect, particularly in leukemia and neuroblastoma. Iron-depletion strategies using iron chelators have been shown to result in cell cycle arrest and apoptosis. Deferoxamine (DFO) was the first FDA-approved drug for the treatment of iron overload pathologies, and has also been recognized as having anticancer properties. The high cost, low permeability and short plasma half-life of DFO led to the development of other iron-chelating drugs. Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs chelate cellular iron by tridentate binding, and inhibit DNA synthesis more robustly than DFO, demonstrating an effective antiproliferative activity. Here, we investigated the biological effects of a PIH derivative, 3-chloro-N′-(2-hydroxybenzylidene)benzohydrazide (CHBH), known to be a lysine-specific histone demethylase 1A inhibitor. We showed that CHBH is able to induce cell proliferation arrest in several human cancer cell lines, including lung, colon, pancreas and breast cancer, at micromolar levels. Our findings indicate that CHBH exerts a dual anticancer action by strongly impairing iron metabolism and modulating chromatin structure and function.

A New Family of Jumonji C Domain-Containing KDM Inhibitors Inspired by Natural Product Purpurogallin

“…Assay was performed as previously described using a KDM4A Inhibitor Enzymatic Assay KIT (Epi-C, Naples, Italy) (Franci et al, 2017;Sarno et al, 2018), and by JMJD2A (KDM4A) Homogeneous Assay Kit (#50413; BPS Bioscience, Milan, Italy). In KDM4A Inhibitor Enzymatic Assay KIT by Epi-C, the compounds (6 µL) were incubated for 30 min at 37 • C with 24 µL of enzymatic solution in a 96-well black half-area plate.…”

Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” It

“…Furthermore, a tissue microarray analysis from 75 breast cancer patients revelated that high G9a expression and low hephaestin expression are associated with poor prognosis [ 78 ]. Interestingly, iron-chelating agents including deferoxamine (DFO), deferasirox (DFX), and their synthetic derivatives inhibit epigenetic JumonjiC domain-containing histone lysine demethylases (JmjC KDMs) which are Fe(II)/2-oxoglutarate-dependent oxygenases that are also involved in transcriptional regulation and DNA repair [ 79 , 80 ]. The first demonstration has been performed by Cao et al, showing that DFO induced a significant increase in global histone methylation in colorectal cancer, leading to the dysregulation of many cell growth-related genes [ 81 ].…”

A Promising Future of Ferroptosis in Tumor Therapy

“…Intracellular iron accumulation may accelerate lung tumorigenesis and development ( Aleman et al, 2002 ). Reducing iron levels with DFX, and its analogs, inhibits tumor growth by limiting iron provision ( Sarno et al, 2018 ). These results were favored by researchers who demonstrated that iron chelators can suppress the growth of human lung tumor xenografts ( Lui et al, 2013 ).…”