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...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-023-03054-x |
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| author | Mariola Gimła Agnieszka Pyrczak-Felczykowska Marcelina Malinowska Aleksandra Hać Magdalena Narajczyk Irena Bylińska Tristan A. Reekie Anna Herman-Antosiewicz |
| author_facet | Mariola Gimła Agnieszka Pyrczak-Felczykowska Marcelina Malinowska Aleksandra Hać Magdalena Narajczyk Irena Bylińska Tristan A. Reekie Anna Herman-Antosiewicz |
| author_sort | Mariola Gimła |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:01:08Z |
| format | Article |
| id | doaj.art-a79a4e7d4fe2412fbfbf03f33d37247b |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-10T17:01:08Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-a79a4e7d4fe2412fbfbf03f33d37247b2023-11-20T10:59:13ZengBMCCancer Cell International1475-28672023-09-0123111310.1186/s12935-023-03054-xThe pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivoMariola Gimła0Agnieszka Pyrczak-Felczykowska1Marcelina Malinowska2Aleksandra Hać3Magdalena Narajczyk4Irena Bylińska5Tristan A. Reekie6Anna Herman-Antosiewicz7Department of Medical Biology and Genetics, Faculty of Biology, University of GdańskDepartment of Physiology, Medical University of GdańskDepartment of Medical Biology and Genetics, Faculty of Biology, University of GdańskDepartment of Medical Biology and Genetics, Faculty of Biology, University of GdańskElectron Microscopy Section, Faculty of Biology, University of GdańskDepartment of Biomedical Chemistry, Faculty of Chemistry, University of GdańskSchool of Science, University of New South Wales Canberra, Australian Capital TerritoryDepartment of Medical Biology and Genetics, Faculty of Biology, University of GdańskAbstract 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.https://doi.org/10.1186/s12935-023-03054-xCancerUsnic acidEndoplasmic reticulum stressCell deathLichensVacuolization |
| spellingShingle | Mariola Gimła Agnieszka Pyrczak-Felczykowska Marcelina Malinowska Aleksandra Hać Magdalena Narajczyk Irena Bylińska Tristan A. Reekie Anna Herman-Antosiewicz The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo Cancer Cell International Cancer Usnic acid Endoplasmic reticulum stress Cell death Lichens Vacuolization |
| title | The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| title_full | The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| title_fullStr | The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| title_full_unstemmed | The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| title_short | The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| title_sort | pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo |
| topic | Cancer Usnic acid Endoplasmic reticulum stress Cell death Lichens Vacuolization |
| url | https://doi.org/10.1186/s12935-023-03054-x |
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