Gimła Mariola, Pyrczak-Felczykowska Agnieszka, Malinowska Marcelina, Hać Aleksandra, Narajczyk Magdalena, Bylińska Irena, Reekie Tristan A, Herman-Antosiewicz Anna
Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland.
Department of Physiology, Medical University of Gdańsk, 80-211, Gdańsk, Poland.
Cancer Cell Int. 2023 Sep 24;23(1):210. doi: 10.1186/s12935-023-03054-x.
Pancreatic cancer is one of the leading causes of cancer death in Western societies. Its late diagnosis and resistance to chemotherapies result in a high mortality rate; thus, the development of more effective therapies for the treatment of pancreatic cancer is strongly warranted. Usnic acid (UA) is a secondary metabolite of lichens that shows modest antiproliferative activity toward cancer cells. Recently, we reported the synthesis of a UA pyrazole derivative, named 5, which was more active than the parent compound toward cervical cancer cells. Here, its anticancer potential has been evaluated in detail in other cancer cells, particularly pancreatic cancer cells.
The impact of UA and derivative 5 on cell viability, morphology, cell cycle, and death was assessed using the MTT test, electron microscopy, flow cytometry, and immunoblotting, respectively. The calcium ions level was detected fluorometrically. In vivo, the anticancer activity of 5 was evaluated in a murine xenograft model.
Derivative 5 inhibited the viability of different cancer cells. Noncancerous cells were less sensitive. It induced the release of calcium ions from the endoplasmic reticulum (ER) and ER stress, which was manifested by cell vacuolization. It was accompanied by G0/G1 cell cycle arrest and cell death of pancreatic cancer cells. When applied to nude mice with xenografted pancreatic cancer cells, 5 inhibited tumor growth, with no signs of kidney or liver toxicity.
UA derivative 5 is superior to UA inhibiting the growth and proliferation of pancreatic cancer cells. ER stress exaggeration is a mechanism underlying the activity of derivative 5.
胰腺癌是西方社会癌症死亡的主要原因之一。其诊断较晚且对化疗耐药，导致死亡率很高；因此，迫切需要开发更有效的胰腺癌治疗方法。松萝酸（UA）是地衣的一种次生代谢产物，对癌细胞显示出适度的抗增殖活性。最近，我们报道了一种UA吡唑衍生物（命名为5）的合成，它对宫颈癌细胞的活性比母体化合物更高。在此，我们详细评估了它在其他癌细胞，特别是胰腺癌细胞中的抗癌潜力。
分别使用MTT试验、电子显微镜、流式细胞术和免疫印迹法评估UA和衍生物5对细胞活力、形态、细胞周期和死亡的影响。通过荧光法检测钙离子水平。在体内，在小鼠异种移植模型中评估5的抗癌活性。
衍生物5抑制了不同癌细胞的活力。非癌细胞敏感性较低。它诱导内质网（ER）释放钙离子并引发内质网应激，表现为细胞空泡化。同时伴有G0/G1期细胞周期阻滞和胰腺癌细胞死亡。当应用于移植了胰腺癌细胞的裸鼠时，5抑制了肿瘤生长，且没有肾脏或肝脏毒性的迹象。
UA衍生物5在抑制胰腺癌细胞生长和增殖方面优于UA。内质网应激加剧是衍生物5发挥活性的一种机制。
