Kozak Yuliia, Finiuk Nataliya, Czarnomysy Robert, Gornowicz Agnieszka, Pinyazhko Roman, Lozynskyi Andrii, Holota Serhii, Klyuchivska Olga, Karkhut Andriy, Polovkovych Svyatoslav, Klishch Mykola, Stoika Rostyslav, Lesyk Roman, Bielawski Krzysztof, Bielawska Anna
Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology of National Academy of Sciences of Ukraine, Drahomanov 14/16, 79005 Lviv, Ukraine.
Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Bialystok, Kilinskiego 1, 15-089 Białystok, Poland.
Cells. 2025 Mar 20;14(6):465. doi: 10.3390/cells14060465.
Colorectal cancer is a major global health challenge, with current treatments limited by toxicity and resistance. Thiazole derivatives, known for their bioactivity, are emerging as promising alternatives. Juglone (5-hydroxy-1,4-naphthoquinone) is a naturally occurring compound with known anticancer properties, and its incorporation into thiopyrano[2,3-d]thiazole scaffolds may enhance their therapeutic potential. This study examined the cytotoxicity of thiopyrano[2,3-d]thiazoles and their effects on apoptosis in colorectal cancer cells. Les-6547 and Les-6557 increased the population of ROS-positive HT-29 cancer cells approximately 10-fold compared with control cells (36.3% and 38.5% vs. 3.8%, respectively), potentially contributing to various downstream effects. Elevated ROS levels were associated with cell cycle arrest, inhibition of DNA biosynthesis, and reduced cell proliferation. A significant shift in the cell cycle distribution was observed, with an increase in S-phase (from 17.3% in the control to 34.7% to 51.3% for Les-6547 and Les-6557, respectively) and G2/M phase (from 24.3% to 39.9% and 28.8%). Additionally, Les-6547 and Les-6557 inhibited DNA biosynthesis in HT-29 cells, with IC values of 2.21 µM and 2.91 µM, respectively. Additionally, ROS generation may initiate the intrinsic apoptotic pathway. and activated both intrinsic and extrinsic apoptotic pathways, demonstrated by notable increases in the activity of caspase 3/7, 8, 9, and 10. This study provides a robust basis for investigating the detailed molecular mechanisms of action and therapeutic potential of Les-6547 and Les-6557.
结直肠癌是一项重大的全球健康挑战，当前的治疗方法受到毒性和耐药性的限制。噻唑衍生物以其生物活性而闻名，正成为有前景的替代方案。胡桃醌（5-羟基-1,4-萘醌）是一种具有已知抗癌特性的天然化合物，将其引入硫代吡喃并[2,3-d]噻唑支架中可能会增强其治疗潜力。本研究考察了硫代吡喃并[2,3-d]噻唑的细胞毒性及其对结直肠癌细胞凋亡的影响。与对照细胞相比，Les-6547和Les-6557使ROS阳性的HT-29癌细胞数量增加了约10倍（分别为36.3%和38.5%，而对照为3.8%），这可能导致各种下游效应。ROS水平升高与细胞周期停滞、DNA生物合成抑制和细胞增殖减少有关。观察到细胞周期分布发生了显著变化，S期增加（从对照的17.3%分别增加到Les-6547和Les-6557的34.7%至51.3%）以及G2/M期增加（从24.3%增加到39.9%和28.8%）。此外，Les-6547和Les-6557抑制HT-29细胞中的DNA生物合成，IC值分别为2.21 μM和2.91 μM。此外，ROS的产生可能启动内源性凋亡途径。Les-6547和Les-6557激活了内源性和外源性凋亡途径，这通过半胱天冬酶3/7、8、9和10活性的显著增加得以证明。本研究为研究Les-6547和Les-6557详细的分子作用机制和治疗潜力提供了有力依据。
