The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

The dual effect of endoplasmic reticulum stress in digestive system tumors and intervention of Chinese botanical drug extracts: a review

“…Usnic acid, a furan metabolite derived from the botanical drug Usnea diffracta Vain, has anti-inflammatory and anti-tumor effects ( Xie LS et al, 2023 ). Gimła M et al (2023) demonstrated that usnic acid upregulated the expression of BIP, IRE1α and GADD153 in human PDA cells MIA PaCa-2 and PANC-1, blocking the cell cycle at G0/G1, inhibiting tumor growth and inducing apoptosis.…”

miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability

“…Although the therapeutic intervention for PC has improved, tumor-related deaths caused by metastasis and recurrence remain a major challenge [ 4 ]. Once PC is diagnosed, the vast majority of cases show distant metastasis [ 5 ]. In addition, PC is less sensitive to radiotherapy, chemotherapy, and immunotherapy because of its intra-tumoral heterogeneity in cell metabolism, which is important for tumor growth and metastasis [ 6 ].…”