Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo

Abstract

The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137’s cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.

Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins

“…CBL0137 in the range of concentration of 5–30 μM decreases DNMT3a binding with DNA, and in the range of concentration of 10–60 μM, it decreases the efficacy of DNA methylation [ 30 ]. CBL0137 revealed remarkable anticancer activity in vitro and in vivo in the model of acute myeloid leukemia (AML) [ 13 ]. This malignancy is characterized by DNMT3A mutations, leading to changes in the DNA methylation profile [ 31 ].…”

“…The experiment was carried out at least five times. For HT29 and HeLa TI cells, we used the nontoxic concentrations determined in previous studies [ 13 , 19 ].…”

“…CBL0137 [1,1 -(9-(2-(isopropylamino)ethyl)-9H-carbazole-3,6-diyl)bis(ethan-1-one)] is a low-molecular-weight nongenotoxic DNA-binding compound from the class of carbazoles referred to as the second generation of Curaxines [12]. CBL0137 possesses a broad spectrum of anticancer effects, which was confirmed in more than 50 preclinical studies [13][14][15][16][17]. Currently, CBL0137 is involved in Phase I-II clinical trials for the treatment of glioblastoma, melanoma, sarcoma, lymphoma, and some other types of cancer (NCT04870944, NCT03727789, and NCT05498792).…”