A review of the mutagenic potential of N‐ethyl‐N‐nitrosourea (ENU) to induce hematological malignancies

Abstract

This review is intended to summarize the existing literature on the mutagenicity of N-ethyl-N-nitrosourea (ENU) in inducing hematological malignancies, including acute myeloid leukemia (AML) in mice. Blood or hematological malignancies are the most common malignant disorders seen in people of all age groups. Driven by a number of genetic alterations, leukemia rule out the normal proliferation and differentiation of hematopoietic stem cells (HSCs) and their progenitors in the bone marrow (BM) and severely affects blood functions. Out of all hematological malignancies, AML is the most aggressive type, with a high incidence and mortality rate. AML is found as either de novo or secondary therapeutic AML (t-AML). t-AML is a serious adverse consequence of alkylator chemotherapy to the cancer patient and alone constitutes about 10%−20% of all reported AML cases. Cancer patients who received alkylator chemotherapy are at an elevated risk of developing t-AML. ENU has a long history of use as a potent carcinogen that induces blood malignancies in mice and rats that are pathologically similar to human AML and t-AML. ENU, once entered into the body, circulates all over the body tissues and reaches BM. It creates an overall state of suppression within the BM by damaging the marrow cells, alkylating the DNA, and forming DNA adducts within the early and late hematopoietic stem and progenitor cells. The BM holds a weak DNA repair mechanism due to low alkyltransferase, and poly [ADP-ribose] polymerase (PARP) enzyme content often fails to obliterate those adducts, acting as a catalyst to bring genetic abnormalities, including point gene mutations as well as chromosomal alterations, for example, translocation and inversion. Taking advantage of ENU-induced immune-suppressed state and weak immune surveillance, these mutations remain viable and slowly give rise to transformed HSCs. This review also highlights the carcinogenic nature of ENU and the complex relation between the ENU's overall toxicity in the induction of hematological malignancies.

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

“…The structures of the target compounds 8a-j were confirmed by spectral data, including different spectroscopic techniques. 1 H NMR spectra showed the characteristics of two ═C-H protons at δ 7.05-7.64 ppm attributed to styryl moiety with J = 15.4-16.0 Hz, which confirms the trans geometry of styryl moiety at position 2 and chalcone protons at δ 7.79-8.09 ppm with J = 15.2-15.7 Hz, which also indicates trans geometry. Increasing the integration of aromatic protons attributed to the additional phenyl rings was recognized and appeared in the 1 H NMR spectra.…”

“…The Shimadzu fourier-transform infrared (FT-IR) spectrometer Affinity A1 was used to record IR spectra as films on KBr plates. The reaction's progress was monitored using thin-layer chromatography (Merck) and visualized by UV Lamp 254 nm 1. H NMR and13 C NMR spectra were measured on a Bruker Avance III 400 MHz for 1 H NMR and 100 MHz for13 C NMR (Bruker AG) with BBFO Smart Probe and Bruker 400 AEON Nitrogen-Free Magnet, Faculty of Pharmacy, Beni-Suef University, Egypt, in DMSO-d 6 with tetramethyl silane as the internal standard, where J (coupling constant) values are estimated in Hertz (Hz) and chemical shifts were recorded in ppm on δ scale and signals expressed as s, d, t, and m. Elemental analyses were recorded on Shimadzu GC/ MS-QP5050A, Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.…”

Vanillic acid protects mortality and toxicity induced by N-ethyl-N-nitrosourea in mice; in vivo model of chronic lymphocytic leukemia

“…Therefore, ROS formation can play an integral role in carcinogenesis and the development of various cancers after exposure with chemical carcinogens [35] . It is well established that alkylating agents such as ENU contribute to carcinogenesis and toxicity via induction of oxidative stress due to increase in reactive oxygen and nitrogen species, glutathione depletion and lipid peroxidation [6] , [36] . Our results consistent with these studies showed that ENU as a full carcinogen agent induces ROS formation, MDA production and oxidative stress in lymphocytes as target cells in CLL.…”

N-Ethyl-N-Nitrosourea Induced Leukaemia in a Mouse Model: Protective Effect of Icaritin via Inhibition of IL-6/JAK2/STAT3 Pathway Causes Apoptosis

“… 29 Specifically, nitrosoureas like n-ethyl-n-nitrosourea (ENU) have been found to induce leukemia by alkylating nucleobases, disrupting DNA, and resulting in bone marrow suppression and the formation of leukemic cells. 30 , 31 ENU has also been observed to generate malignant cells in the brain and reproductive system in animal models. 4 , 32 Any disruption in the signaling cascade that regulates differentiation and proliferation can lead to hematological abnormalities, resulting in a buildup of cancerous cells in the bone marrow and blood.…”