Cytotoxic and immunomodulatory potential of a novel [2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)−1H-pyrazol-3-yl)pyridine] in myeloid leukemia

• Published in: Biomedicine & pharmacotherapy 2023-06, Vol.162, p.114701-114701, Article 114701
• Main Authors: de Castro Alves, Carlos Eduardo, Koidan, Georgyi, Hurieva, Anastasiia N., de Freitas Gomes, Alice, Costa de Oliveira, Regiane, Guimarães Costa, Allyson, Ribeiro Boechat, Antônio Luiz, Correa de Oliveira, André, Zahorulko, Serhii, Kostyuk, Aleksandr, Soares Pontes, Gemilson
• Format: Article
• Language: English
• Subjects: Animals; Anticancer; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Chlorocebus aethiops; Humans; Immunomodulation; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Myeloid leukemia; Pyridine synthesis; Pyridines; Vero Cells
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114701

Cancer ranks among the leading causes of mortality worldwide. However, the efficacy of commercially available anticancer drugs is compromised by the emerging challenge of drug resistance. This study aimed to investigate the anticancer and immunomodulatory potential of a recently developed a novel [2-(4-(2,5-dimethyl-1 H-pyrrol-1-yl)− 1 H-pyrazol-3-yl) pyridine]. The cytotoxic potential of the compound was assessed using the MTT assay on both cancerous HL60 (acute myeloid leukemia) and K562 (chronic myeloid leukemia) cell lines, as well as non-cancerous Vero cells and human peripheral blood mononuclear cells (PBMCs). A clonogenic assay was employed to evaluate the anticancer efficacy of the compound, while flow cytometry was utilized to investigate its effect on cell cycle arrest. Furthermore, the immunomodulatory potential of the compound was assessed by quantifying inflammatory and anti-inflammatory biomarkers in the supernatant of PBMCs previously treated with the compound. Our study revealed that the novel pyridine ensemble exhibits selective cytotoxicity against HL60 (IC50 = 25.93 µg/mL) and K562 (IC50 = 10.42 µg/mL) cell lines, while displaying no significant cytotoxic effect on non-cancerous cells. In addition, the compound induced a decrease of 18% and 19% in the overall activity of COX-1 and COX-2, respectively. Concurrently, it upregulated the expression of cytokines including IL4, IL6, IL10, and IL12/23p40, while downregulating INFγ expression. These findings suggest that the compound has the potential to serve as a promising candidate for the treatment of acute and chronic myeloid leukemias due to its effective antiproliferative and immunomodulatory activities, without causing cytotoxicity in non-cancerous cells. [Display omitted] •The novel pyridine ensemble (compound 3) selectively inhibits cancerous cell growth.•Compound 3 induces S and G2 phase cell cycle arrest, causing genomic instability and apoptosis in leukemia cells.•Compound 3 may block prostaglandin synthesis by inhibiting COX-1 and COX-2 enzymes.•Compound 3 may modulate immunity in myeloid malignancies by upregulating IL4, IL6, IL12/23p40 and downregulating INFγ.