Farmakis Danae, Stravopodis Dimitrios J, Prombona Anastasia
Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, Zografou, 157 01 Athens, Greece.
Laboratory of Chronobiology, Institute of Biosciences and Applications (IBA), National Centre for Scientific Research (NCSR) "Demokritos", 153 41 Aghia Paraskevi, Greece.
Int J Mol Sci. 2024 Dec 28;26(1):178. doi: 10.3390/ijms26010178.
: Pancreatic Ductal Adeno-Carcinoma (PDAC) is a highly aggressive cancer, with limited treatment options. Disruption of the circadian clock, which regulates key cellular processes, has been implicated in PDAC initiation and progression. Hence, targeting circadian clock components may offer new therapeutic opportunities for the disease. This study investigates the cytopathic effects of TH301, a novel CRY2 stabilizer, on PDAC cells, aiming to evaluate its potential as a novel therapeutic agent. : PDAC cell lines (AsPC-1, BxPC-3 and PANC-1) were treated with TH301, and cell viability, cell cycle progression, apoptosis, autophagy, circadian gene, and protein expression profiles were analyzed, using MTT assay, flow cytometry, Western blotting, and RT-qPCR technologies. : TH301 proved to significantly decrease cell viability and to induce cell cycle arrest at the G1-phase across all PDAC cell lines herein examined, especially the AsPC-1 and BxPC-3 ones. It caused dose-dependent apoptosis and autophagy, and it synergized with Chloroquine and Oxaliplatin to enhance anti-oncogenicity. The remarkable induction of p21 by TH301 was shown to follow clock- and p53-independent patterns, thereby indicating the critical engagement of alternative mechanisms. : TH301 demonstrates significant anti-cancer activities in PDAC cells, thus serving as a promising new therapeutic agent, which can also synergize with approved treatment schemes by targeting pathways beyond circadian clock regulation. Altogether, TH301 likely opens new therapeutic windows for the successful management of pancreatic cancer in clinical practice.
胰腺导管腺癌（PDAC）是一种侵袭性很强的癌症，治疗选择有限。调节关键细胞过程的生物钟紊乱与PDAC的发生和发展有关。因此，靶向生物钟组件可能为该疾病提供新的治疗机会。本研究调查了新型CRY2稳定剂TH301对PDAC细胞的细胞病变效应，旨在评估其作为新型治疗剂的潜力。使用MTT法、流式细胞术、蛋白质印迹法和RT-qPCR技术，用TH301处理PDAC细胞系（AsPC-1、BxPC-3和PANC-1），并分析细胞活力、细胞周期进程、凋亡、自噬、生物钟基因和蛋白质表达谱。结果表明，TH301能显著降低所有受试PDAC细胞系的细胞活力，并诱导细胞周期在G1期停滞，尤其是AsPC-1和BxPC-3细胞系。它引起剂量依赖性凋亡和自噬，并与氯喹和奥沙利铂协同增强抗癌作用。TH301对p21的显著诱导显示出不依赖生物钟和p53的模式，从而表明替代机制的关键参与。TH301在PDAC细胞中表现出显著的抗癌活性，因此是一种有前景的新型治疗剂，它还可以通过靶向生物钟调节以外的途径与已批准的治疗方案协同作用。总之，TH301可能为临床实践中成功治疗胰腺癌打开新的治疗窗口。
