Effects of Usnic Acid on Cytotoxicity, Colony Formation and Migration in SK-UT-1 Human Uterine Leiomyosarcoma Cells
Year 2023,
, 195 - 202, 23.11.2023
Doğukan Mutlu
,
Mücahit Seçme
,
Şevki Arslan
Abstract
Usnic acid (UA) is a common lichenic secondary metabolite with therapeutic potential. Anticancer, antimicrobial, and antioxidant effects have been demonstrated and UA-enriched extracts are often used to treat various diseases in traditional medicine. First, we performed a viability assay of UA in human uterine leiomyosarcoma (SK-UT-1) since no in vitro cytotoxicity data have been reported so far. For this purpose, the cytotoxicity of UA on SK-UT-1 and embryonic kidney (HEK293) cells was studied at 24 and 48 hours. The toxicity of UA was investigated by the MTT test. In addition, we assessed UA colony formation and migration properties against SK-UT-1 cells in 6-well plates. Our results showed a significant cytotoxic effect of UA at the 5.34 µM; UA was also effective against colony formation ability and wound healing assay. In conclusion, our study suggests that UA exerts anti-proliferative effects on SK-UT-1 cells by inducing cell death. Moreover, our results suggest that the potential anticancer activities of UA should be further studied by additional molecular biological approaches.
References
- E. D'Angelo, J. Prat, “Uterine sarcomas: a review”, Gynecologic oncology, 116(1), 131-139, 2010.
- R. L. Giuntoli, D. S. Metzinger, C. S. DiMarco, S. S. Cha, J. A. Sloan, G. L. Keeney and B. S. Gostout, “Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy”, Gynecologic oncology, 89(3), 460-469, 2003.
- E. Fujimoto, K. Takehara, T. Tanaka, T. Yokoyama, K. Tomono, M.Okazawa-Sakai, S. Okame, Y. Sugawara and N. Teramoto, “Uterine leiomyosarcoma well-controlled with eribulin mesylate”, International cancer conference journal, (8)1, 33-38, 2018.
- M. Azumi, M. Yoshie, N. Nakachi, A. Tsuru, K. Kusama and K. Tamura, “Stathmin expression alters the antiproliferative effect of eribulin in leiomyosarcoma cells”, Journal of pharmacological sciences, 150(4), 259-266, 2022.
- A. Pistilli, M. Rende, L. Crispoltoni, C. Montagnoli and A. M. Stabile, “LY294002 induces in vitro apoptosis and overexpression of p75NTR in human uterine leiomyosarcoma HTB 114 cells”, Growth factors (Chur, Switzerland), 33(5-6), 376-383, 2015.
- O. Mosunova, J. C. Navarro-Muñoz and J. Collemare, “The biosynthesis of fungal secondary metabolites: From fundamentals to biotechnological applications”, In Encyclopedia of Mycology, 2, 458-476, 2021.
- A. M. L. Seca and D. C. G. A. Pinto, “Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application”, International Journal of Molecular Sciences, 19(1), 263, 2018.
- S. Bhattacharyya, P. R. Deep, S. Singh and B. Nayak, “Lichen Secondary Metabolites and Its Biological Activity”, American Journal of Pharmtech Research, 6(6), 29-44, 2016.
- F. Salgado, L. Albornoz, C. Cortéz, E. Stashenko, K. Urrea-Vallejo, E. Nagles, C. Galicia-Virviescas, A. Cornejo, A. Ardiles, M. Simirgiotis, O. García-Beltrán, and C. Areche, “Secondary Metabolite Profiling of Species of the Genus Usnea by UHPLC-ESI-OT-MS-MS”, Molecules (Basel, Switzerland), 23(1), 54, 2017.
- H. Wang, M. Xuan, C. Huang and C. Wang, “Advances in Research on Bioactivity, Toxicity, Metabolism, and Pharmacokinetics of UA In Vitro and In Vivo”, Molecules (Basel, Switzerland), 27(21), 7469, 2022.
- A. A. Araújo, M. G. de Melo, T. K. Rabelo, P. S. Nunes, S. L. Santos, M. R. Serafini, M. R. J Santos, L. J. Quintans-Júnior and D. P. Gelain, “Review of the biological properties and toxicity of UA”, Natural product research, 29(23), 2167-2180, 2015.
- M. Secme and Y. Dodurga, “UA Inhibits Cell Proliferation and Downregulates lncRNA UCA1 Expression in Ishikawa Endometrial Cancer Cells”, Natural Products and Biotechnology, 1(1), 28-37, 2021.
- W. Qi, C. Lu, H. Huang, W. Zhang, S. Song and B. Liu, “(+)-UA Induces ROS-dependent Apoptosis via Inhibition of Mitochondria Respiratory Chain Complexes and Nrf2 Expression in Lung Squamous Cell Carcinoma”, International journal of molecular sciences, 21(3), 876, 2020.
- N. Kilic, Y. O. Islakoglu, I. Buyuk, B. Gur-Dedeoglu and D. Cansaran-Duman, “Determination of UA Responsive miRNAs in Breast Cancer Cell Lines”, Anti-cancer agents in medicinal chemistry, 19(12), 1463-1472, 2019.
- L. Samuelsen, P. E. Hansen and O. Vang, “Derivatives of UA cause cytostatic effect in Caco-2 cells”, Natural product research, 35(23), 4953-4959, 2021.
- S. Wang, J. Zang, M. Huang, L. Guan, K. Xing, J. Zhang, D. Liu and L. Zhao, “Discovery of novel (+)-UA derivatives as potential anti-leukemia agents with pan-Pim kinases inhibitory activity”, Bioorganic chemistry, 89, 102971, 2019.
- K. Kumar, J. P. N. Mishra and R. P. Singh, “UA induces apoptosis in human gastric cancer cells through ROS generation and DNA damage and causes up-regulation of DNA-PKcs and γ-H2A.X phosphorylation”, Chemico-biological interactions, 315, 108898, 2020.
- A. Galanty, P. Koczurkiewicz, D. Wnuk, M. Paw, E. Karnas, I. Podolak, M. Węgrzyn, M. Borusiewicz, Z. Madeja, J. Czyż and M. Michalik, “UA and atranorin exert selective cytostatic and anti-invasive effects on human prostate and melanoma cancer cells”, Toxicology in vitro, 40, 161-169, 2017.
- C. Yilmaz, S. Arslan, D. Mutlu, M. Konus, A. Kayhan, A. Kurt-Kizildogan, C. Otur, O. Ozok, and A. Kivrak, “Identification of 3-Bromo-1-Ethyl-1H-Indole as a Potent Anticancer Agent with Promising Inhibitory Effects on GST Isozymes”, Anti-Cancer Agents in Medicinal Chemistry, 21(10), 1292-1300, 2021.
- E. Kavak, D. Mutlu, O. Ozok, S. Arslan and A. Kivrak, “Design, synthesis and pharmacological evaluation of novel Artemisinin-Thymol”, Natural Product Research, 36(14), 3511-3519, 2022.
- D. Mutlu, C. Cakir, M. Ozturk and S. Arslan, “Anticancer and apoptotic effects of a polysaccharide extract isolated from Lactarius chrysorrheus Fr. in HepG2 and PANC-1 cell lines”, Archives of Biological Sciences, 74(4), 315-324, 2022.
- S. T. Zuo, L. P. Wang, Y. Zhang, D. N. Zhao, Q. S. Li, D. Shao and X. D. Fang, “Usnic acid induces apoptosis via an ROS-dependent mitochondrial pathway in human breast cancer cells in vitro and in vivo”, RSC Advances, 5(1), 153-162, 2015.
- W. Wu, H. Gou, J. Dong, X. Yang, Y. Zhao, H. Peng, D. Chen, R. Geng, L. Chen and J. Liu, “Usnic Acid Inhibits Proliferation and Migration through ATM Mediated DNA Damage Response in RKO Colorectal Cancer Cell”, Current pharmaceutical biotechnology, 22(8), 1129-1138, 2021.
- Y. Yang, T. T. Nguyen, M. Jeong, F. Crisan, Y. H. Yu, H. Ha, K. H. Choi, H. G. Jeong, T. C. Jeong, K. Y. Lee, K. K. Kim, J. S. Hur and H. Kim, “Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility”, PloS one, 11(1), 2016.
- A. T. Koparal, “Anti-angiogenic and antiproliferative properties of the lichen substances (-)-usnic acid and vulpinic acid. Zeitschrift fur Naturforschung” Journal of biosciences, 70(5-6), 159–164, 2015.
- B. Emsen, A. Aslan, H. Turkez, A. Joughi and A. Kaya, “The anti-cancer efficacies of diffractaic, lobaric, and usnic acid: In vitro inhibition of glioma”, Journal of cancer research and therapeutics, 14(5), 941–951, 2018.
- N. S. Dyrkheeva, A. S. Filimonov, O. A. Luzina, A. L. Zakharenko, E. S. Ilina, A. A. Malakhova, S. P. Medvedev, J. Reynisson, K. P. Volcho, S. M. Zakian, N. F. Salakhutdinov and O. I. Lavrik, “New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition”, Biomolecules,11(7), 973, 2021.
- B. Yurdacan, U. Egeli, G. G. Eskiler, I. E. Eryilmaz, G. Cecener and B. Tunca, "The role of usnic acid-induced apoptosis and autophagy in hepatocellular carcinoma", Human & Experimental Toxicology, 38(2), 201-215, 2019.
- B. Colak, D. Cansaran-Duman, G. G. Eskiler, K. Földes and S. Yangin, "Usnic acid-induced programmed cell death in ovarian cancer cells", Rendiconti Lincei. Scienze Fisiche e Naturali, 33, 143-152, 2022.
- N. Singh, D. Nambiar, R. K. Kale and R. P. Singh, “Usnic acid inhibits growth and induces cell cycle arrest and apoptosis in human lung carcinoma A549 cells”, Nutrition and cancer, 65, 36–43, 2013.
- T. Anuk, B. Yildiz, R. Demirel, M. Icen, S. Yildirim, H. Beseren, B. Mor and O. Ozden, “Usnic acid reduces colon cancer cell viability and colony formation by affecting cancer cell metabolism”, Kafkas Universitesi Veteriner Fakultesi Dergisi, 28(4), 491-497, 2022.
Year 2023,
, 195 - 202, 23.11.2023
Doğukan Mutlu
,
Mücahit Seçme
,
Şevki Arslan
References
- E. D'Angelo, J. Prat, “Uterine sarcomas: a review”, Gynecologic oncology, 116(1), 131-139, 2010.
- R. L. Giuntoli, D. S. Metzinger, C. S. DiMarco, S. S. Cha, J. A. Sloan, G. L. Keeney and B. S. Gostout, “Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy”, Gynecologic oncology, 89(3), 460-469, 2003.
- E. Fujimoto, K. Takehara, T. Tanaka, T. Yokoyama, K. Tomono, M.Okazawa-Sakai, S. Okame, Y. Sugawara and N. Teramoto, “Uterine leiomyosarcoma well-controlled with eribulin mesylate”, International cancer conference journal, (8)1, 33-38, 2018.
- M. Azumi, M. Yoshie, N. Nakachi, A. Tsuru, K. Kusama and K. Tamura, “Stathmin expression alters the antiproliferative effect of eribulin in leiomyosarcoma cells”, Journal of pharmacological sciences, 150(4), 259-266, 2022.
- A. Pistilli, M. Rende, L. Crispoltoni, C. Montagnoli and A. M. Stabile, “LY294002 induces in vitro apoptosis and overexpression of p75NTR in human uterine leiomyosarcoma HTB 114 cells”, Growth factors (Chur, Switzerland), 33(5-6), 376-383, 2015.
- O. Mosunova, J. C. Navarro-Muñoz and J. Collemare, “The biosynthesis of fungal secondary metabolites: From fundamentals to biotechnological applications”, In Encyclopedia of Mycology, 2, 458-476, 2021.
- A. M. L. Seca and D. C. G. A. Pinto, “Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application”, International Journal of Molecular Sciences, 19(1), 263, 2018.
- S. Bhattacharyya, P. R. Deep, S. Singh and B. Nayak, “Lichen Secondary Metabolites and Its Biological Activity”, American Journal of Pharmtech Research, 6(6), 29-44, 2016.
- F. Salgado, L. Albornoz, C. Cortéz, E. Stashenko, K. Urrea-Vallejo, E. Nagles, C. Galicia-Virviescas, A. Cornejo, A. Ardiles, M. Simirgiotis, O. García-Beltrán, and C. Areche, “Secondary Metabolite Profiling of Species of the Genus Usnea by UHPLC-ESI-OT-MS-MS”, Molecules (Basel, Switzerland), 23(1), 54, 2017.
- H. Wang, M. Xuan, C. Huang and C. Wang, “Advances in Research on Bioactivity, Toxicity, Metabolism, and Pharmacokinetics of UA In Vitro and In Vivo”, Molecules (Basel, Switzerland), 27(21), 7469, 2022.
- A. A. Araújo, M. G. de Melo, T. K. Rabelo, P. S. Nunes, S. L. Santos, M. R. Serafini, M. R. J Santos, L. J. Quintans-Júnior and D. P. Gelain, “Review of the biological properties and toxicity of UA”, Natural product research, 29(23), 2167-2180, 2015.
- M. Secme and Y. Dodurga, “UA Inhibits Cell Proliferation and Downregulates lncRNA UCA1 Expression in Ishikawa Endometrial Cancer Cells”, Natural Products and Biotechnology, 1(1), 28-37, 2021.
- W. Qi, C. Lu, H. Huang, W. Zhang, S. Song and B. Liu, “(+)-UA Induces ROS-dependent Apoptosis via Inhibition of Mitochondria Respiratory Chain Complexes and Nrf2 Expression in Lung Squamous Cell Carcinoma”, International journal of molecular sciences, 21(3), 876, 2020.
- N. Kilic, Y. O. Islakoglu, I. Buyuk, B. Gur-Dedeoglu and D. Cansaran-Duman, “Determination of UA Responsive miRNAs in Breast Cancer Cell Lines”, Anti-cancer agents in medicinal chemistry, 19(12), 1463-1472, 2019.
- L. Samuelsen, P. E. Hansen and O. Vang, “Derivatives of UA cause cytostatic effect in Caco-2 cells”, Natural product research, 35(23), 4953-4959, 2021.
- S. Wang, J. Zang, M. Huang, L. Guan, K. Xing, J. Zhang, D. Liu and L. Zhao, “Discovery of novel (+)-UA derivatives as potential anti-leukemia agents with pan-Pim kinases inhibitory activity”, Bioorganic chemistry, 89, 102971, 2019.
- K. Kumar, J. P. N. Mishra and R. P. Singh, “UA induces apoptosis in human gastric cancer cells through ROS generation and DNA damage and causes up-regulation of DNA-PKcs and γ-H2A.X phosphorylation”, Chemico-biological interactions, 315, 108898, 2020.
- A. Galanty, P. Koczurkiewicz, D. Wnuk, M. Paw, E. Karnas, I. Podolak, M. Węgrzyn, M. Borusiewicz, Z. Madeja, J. Czyż and M. Michalik, “UA and atranorin exert selective cytostatic and anti-invasive effects on human prostate and melanoma cancer cells”, Toxicology in vitro, 40, 161-169, 2017.
- C. Yilmaz, S. Arslan, D. Mutlu, M. Konus, A. Kayhan, A. Kurt-Kizildogan, C. Otur, O. Ozok, and A. Kivrak, “Identification of 3-Bromo-1-Ethyl-1H-Indole as a Potent Anticancer Agent with Promising Inhibitory Effects on GST Isozymes”, Anti-Cancer Agents in Medicinal Chemistry, 21(10), 1292-1300, 2021.
- E. Kavak, D. Mutlu, O. Ozok, S. Arslan and A. Kivrak, “Design, synthesis and pharmacological evaluation of novel Artemisinin-Thymol”, Natural Product Research, 36(14), 3511-3519, 2022.
- D. Mutlu, C. Cakir, M. Ozturk and S. Arslan, “Anticancer and apoptotic effects of a polysaccharide extract isolated from Lactarius chrysorrheus Fr. in HepG2 and PANC-1 cell lines”, Archives of Biological Sciences, 74(4), 315-324, 2022.
- S. T. Zuo, L. P. Wang, Y. Zhang, D. N. Zhao, Q. S. Li, D. Shao and X. D. Fang, “Usnic acid induces apoptosis via an ROS-dependent mitochondrial pathway in human breast cancer cells in vitro and in vivo”, RSC Advances, 5(1), 153-162, 2015.
- W. Wu, H. Gou, J. Dong, X. Yang, Y. Zhao, H. Peng, D. Chen, R. Geng, L. Chen and J. Liu, “Usnic Acid Inhibits Proliferation and Migration through ATM Mediated DNA Damage Response in RKO Colorectal Cancer Cell”, Current pharmaceutical biotechnology, 22(8), 1129-1138, 2021.
- Y. Yang, T. T. Nguyen, M. Jeong, F. Crisan, Y. H. Yu, H. Ha, K. H. Choi, H. G. Jeong, T. C. Jeong, K. Y. Lee, K. K. Kim, J. S. Hur and H. Kim, “Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility”, PloS one, 11(1), 2016.
- A. T. Koparal, “Anti-angiogenic and antiproliferative properties of the lichen substances (-)-usnic acid and vulpinic acid. Zeitschrift fur Naturforschung” Journal of biosciences, 70(5-6), 159–164, 2015.
- B. Emsen, A. Aslan, H. Turkez, A. Joughi and A. Kaya, “The anti-cancer efficacies of diffractaic, lobaric, and usnic acid: In vitro inhibition of glioma”, Journal of cancer research and therapeutics, 14(5), 941–951, 2018.
- N. S. Dyrkheeva, A. S. Filimonov, O. A. Luzina, A. L. Zakharenko, E. S. Ilina, A. A. Malakhova, S. P. Medvedev, J. Reynisson, K. P. Volcho, S. M. Zakian, N. F. Salakhutdinov and O. I. Lavrik, “New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition”, Biomolecules,11(7), 973, 2021.
- B. Yurdacan, U. Egeli, G. G. Eskiler, I. E. Eryilmaz, G. Cecener and B. Tunca, "The role of usnic acid-induced apoptosis and autophagy in hepatocellular carcinoma", Human & Experimental Toxicology, 38(2), 201-215, 2019.
- B. Colak, D. Cansaran-Duman, G. G. Eskiler, K. Földes and S. Yangin, "Usnic acid-induced programmed cell death in ovarian cancer cells", Rendiconti Lincei. Scienze Fisiche e Naturali, 33, 143-152, 2022.
- N. Singh, D. Nambiar, R. K. Kale and R. P. Singh, “Usnic acid inhibits growth and induces cell cycle arrest and apoptosis in human lung carcinoma A549 cells”, Nutrition and cancer, 65, 36–43, 2013.
- T. Anuk, B. Yildiz, R. Demirel, M. Icen, S. Yildirim, H. Beseren, B. Mor and O. Ozden, “Usnic acid reduces colon cancer cell viability and colony formation by affecting cancer cell metabolism”, Kafkas Universitesi Veteriner Fakultesi Dergisi, 28(4), 491-497, 2022.