Kowalski Szymon, Wityk Paweł, Raczak-Gutknecht Joanna, Olszewska Anna, Żmijewski Michał, Kocić Ivan
Department of Pharmacology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
Department of Molecular Biotechnology and Microbiology, Faculty of Chemistry, Gdańsk University of Technology, Gdańsk, Poland; Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdańsk, Gdansk, Poland; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Eur J Pharmacol. 2025 Jun 5;996:177590. doi: 10.1016/j.ejphar.2025.177590. Epub 2025 Apr 2.
Recently, interest in imidazoline receptors (IRs) has been increasing. Over the years, a growing number of studies have highlighted the therapeutic potential of ligands targeting these receptors, however, the potential role of imidazoline I receptor agonists in cancer treatment has not been thoroughly investigated. Colorectal cancer (CRC) is among the most prevalent and lethal forms of cancer worldwide. The complexity of CRC necessitates individualized approaches. One promising area of research within CRC therapy is the regulation of autophagy. Recent studies have explored the relationship between autophagy and cancer progression, revealing that autophagy modulation could be a potential strategy for CRC treatment. However, the mechanisms underlying autophagy regulation remain poorly understood. This study aimed to evaluate the effect of the imidazoline I receptor agonist, namely 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI), on colorectal cancer cells, HT-29 and HCT-116 cell lines, particularly its impact when co-incubated with the autophagy inhibitor, hydroxychloroquine (HCQ). The results showed that 2-BFI synergistically increased the cytotoxic effect of HCQ by inducing oxidative stress and apoptosis. Furthermore, our investigation indicated impairment autophagic influx in colon cancer cells treated by 2-BFI. The comprehensive metabolomic analysis revealed significant alterations in key metabolic pathways including MAO activity, oxidative stress responses, energy-related metabolites and amino acids metabolism. Altogether, these findings demonstrate potential a new therapeutic strategy based on autophagy regulation and the selective induction of oxidative stress in colorectal cancer cells. Moreover, this study provides a foundation for further investigation into the therapeutic potential of imidazoline receptor agonists in cancer therapy.
最近，人们对咪唑啉受体（IRs）的兴趣日益增加。多年来，越来越多的研究强调了靶向这些受体的配体的治疗潜力，然而，咪唑啉I受体激动剂在癌症治疗中的潜在作用尚未得到充分研究。结直肠癌（CRC）是全球最常见和最致命的癌症形式之一。CRC的复杂性需要个性化的治疗方法。CRC治疗中一个有前景的研究领域是自噬的调节。最近的研究探讨了自噬与癌症进展之间的关系，表明自噬调节可能是CRC治疗的一种潜在策略。然而，自噬调节的潜在机制仍知之甚少。本研究旨在评估咪唑啉I受体激动剂，即2-（2-苯并呋喃基）-2-咪唑啉盐酸盐（2-BFI）对结肠癌细胞系HT-29和HCT-116的影响，特别是与自噬抑制剂羟氯喹（HCQ）共同孵育时的影响。结果表明，2-BFI通过诱导氧化应激和细胞凋亡协同增强了HCQ的细胞毒性作用。此外，我们的研究表明2-BFI处理的结肠癌细胞中自噬流入受损。综合代谢组学分析揭示了关键代谢途径的显著变化，包括单胺氧化酶（MAO）活性、氧化应激反应、能量相关代谢物和氨基酸代谢。总之，这些发现证明了基于自噬调节和选择性诱导结肠癌细胞氧化应激的潜在新治疗策略。此外，本研究为进一步研究咪唑啉受体激动剂在癌症治疗中的治疗潜力提供了基础。
