Kurdyn Agnieszka, Pawłowska Monika, Paluszkiewicz Ewa, Cichorek Mirosława, Augustin Ewa
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza 11/12, Gdańsk, 80-233, Poland.
Department of Embryology, Medical University of Gdańsk, Dębinki 1, Gdańsk, 80-211, Poland.
Pharmacol Rep. 2025 Feb;77(1):182-209. doi: 10.1007/s43440-024-00658-6. Epub 2024 Oct 3.
Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer.
The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting.
Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs.
UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.
胰腺癌（PC）是侵袭性最强的癌症之一，是全球癌症相关死亡的第七大主要原因。胰腺癌的特点是进展迅速且对传统治疗有抗性。KRAS、CDKN2A、TP53、SMAD4/DPC4和MYC基因的突变是与胰腺癌患者治疗效果不佳相关的主要基因改变。因此，优化胰腺癌治疗是一项巨大挑战。我们团队合成的不对称双吖啶（UAs）是有前景的新型化合物，已显示出对包括胰腺癌在内的多种实体瘤具有高细胞毒性和抗肿瘤活性。
通过MTT法（细胞生长抑制）、流式细胞术以及荧光和光学显微镜（细胞周期分布、凋亡和衰老检测）评估UAs对胰腺癌细胞的细胞效应。通过蛋白质印迹法分析UAs对蛋白质（c-Myc、p53、SMAD4、p21和p16）水平的影响。
凋亡是UAs处理后引发死亡的主要机制，SMAD4蛋白的诱导可促进这一过程。c-Myc是UAs的分子靶点之一，可通过不依赖p53的方式参与细胞死亡的诱导。此外，UAs还可通过上调p21诱导加速衰老。值得注意的是，衰老细胞在长时间暴露于UAs后可通过凋亡死亡。
UAs已成为有效的抗癌剂，通过抑制c-Myc蛋白诱导凋亡，并通过增加p21水平以剂量依赖的方式触发细胞衰老。因此，UAs作为未来胰腺癌抗癌治疗的有前景候选药物具有理想的特性。
