Skip to main content
Erschienen in:

30.09.2022 | original article

Polo-like kinase inhibitor BI2536 induces eryptosis

verfasst von: Dr. Mohamed Jemaà, Raja Mokdad Gargouri, Florian Lang

Erschienen in: Wiener Medizinische Wochenschrift | Ausgabe 5-6/2023

Einloggen, um Zugang zu erhalten

Summary

BI2536 is potent inhibitor of polo-like kinases PLK1, 2, and 3. The inhibition of PLKs in nucleated cells induces apoptosis by perturbing the cell cycle with consequent engagement of mitotic catastrophe. BI2536 is being tested as chemotherapy in various phase I/II/III clinical trials. Erythrocytes do not have a nucleus; however, they may undergo programmed suicide with characteristic hallmarks including cell shrinkage and phosphatidylserine translocation to the cell surface. This particular death is baptized eryptosis. Our study explored whether BI2536 induces eryptosis. We used flow cytometry to access death in red blood cells. We analyzed the cellular volume, the intracellular calcium concentration, the cell surface phosphatidylserine exposure, and the ceramide abundance. In addition, we analyzed the effect of BI2536 on hemolysis. Our investigation showed that after 48 h of incubation with PLK inhibitor BI2536, erythrocytes lost volume and were positive for annexin‑V without any effect on hemolysis. Cells also showed an abundance of ceramide and an increase of intracellular calcium. All these finding suggest that BI2536 provokes eryptosis in red blood cells, ostensibly in part due to Ca2+ entry and ceramide accumulation.
Literatur
1.
Zurück zum Zitat Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004;5:429–40.CrossRefPubMed Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004;5:429–40.CrossRefPubMed
3.
Zurück zum Zitat Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle. 2008;7:3548–55.CrossRefPubMed Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle. 2008;7:3548–55.CrossRefPubMed
4.
Zurück zum Zitat Xie S, et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem. 2001;276:43305–12.CrossRefPubMed Xie S, et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem. 2001;276:43305–12.CrossRefPubMed
5.
Zurück zum Zitat Jemaà M, Kifagi C, Serrano SS, Massoumi R. Preferential killing of tetraploid colon cancer cells by targeting the mitotic Kinase PLK1. Cell Physiol Biochem. 2020;54:303–20.CrossRefPubMed Jemaà M, Kifagi C, Serrano SS, Massoumi R. Preferential killing of tetraploid colon cancer cells by targeting the mitotic Kinase PLK1. Cell Physiol Biochem. 2020;54:303–20.CrossRefPubMed
6.
Zurück zum Zitat Steegmaier M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316–22.CrossRefPubMed Steegmaier M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316–22.CrossRefPubMed
7.
Zurück zum Zitat Manic G, Corradi F, Sistigu A, Siteni S, Vitale I. Molecular regulation of the spindle assembly checkpoint by kinases and phosphatases. Int Rev Cell Mol Biol. 2017;328:105–61.CrossRefPubMed Manic G, Corradi F, Sistigu A, Siteni S, Vitale I. Molecular regulation of the spindle assembly checkpoint by kinases and phosphatases. Int Rev Cell Mol Biol. 2017;328:105–61.CrossRefPubMed
8.
Zurück zum Zitat Jemaà M. Mitotic spindle as therapeutic target for tetraploid cancer cells. Eurasian J Med Oncol. 2021;5(3):205–8. Jemaà M. Mitotic spindle as therapeutic target for tetraploid cancer cells. Eurasian J Med Oncol. 2021;5(3):205–8.
9.
Zurück zum Zitat D’Alessandro A, Dzieciatkowska M, Nemkov T, Hansen KC. Red blood cell proteomics update: Is there more to discover? Blood Transfus. 2017;15:182–7.PubMedPubMedCentral D’Alessandro A, Dzieciatkowska M, Nemkov T, Hansen KC. Red blood cell proteomics update: Is there more to discover? Blood Transfus. 2017;15:182–7.PubMedPubMedCentral
10.
Zurück zum Zitat Garcia-Roa M, et al. Red blood cell storage time and transfusion: current practice, concerns and future perspectives. Blood Transfus. 2017;15:222–31.PubMedPubMedCentral Garcia-Roa M, et al. Red blood cell storage time and transfusion: current practice, concerns and future perspectives. Blood Transfus. 2017;15:222–31.PubMedPubMedCentral
11.
Zurück zum Zitat Mairbaurl H, Weber RE. Oxygen transport by hemoglobin. Compr Physiol. 2012;2:1463–89.CrossRefPubMed Mairbaurl H, Weber RE. Oxygen transport by hemoglobin. Compr Physiol. 2012;2:1463–89.CrossRefPubMed
12.
Zurück zum Zitat Moras M, Lefevre SD, Ostuni MA. From erythroblasts to mature red blood cells: organelle clearance in mammals. Front Physiol. 2017;8:1076.CrossRefPubMedPubMedCentral Moras M, Lefevre SD, Ostuni MA. From erythroblasts to mature red blood cells: organelle clearance in mammals. Front Physiol. 2017;8:1076.CrossRefPubMedPubMedCentral
13.
14.
Zurück zum Zitat Lang E, Lang F. Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. Biomed Res Int. 2015;2015:513518.CrossRefPubMedPubMedCentral Lang E, Lang F. Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. Biomed Res Int. 2015;2015:513518.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Lang F, Jilani K, Lang E. Therapeutic potential of manipulating suicidal erythrocyte death. Expert Opin Ther Targets. 2015;19:1219–27.CrossRefPubMed Lang F, Jilani K, Lang E. Therapeutic potential of manipulating suicidal erythrocyte death. Expert Opin Ther Targets. 2015;19:1219–27.CrossRefPubMed
17.
Zurück zum Zitat Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: a paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. Blood Rev. 2017;31:349–61.CrossRefPubMed Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: a paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. Blood Rev. 2017;31:349–61.CrossRefPubMed
18.
Zurück zum Zitat Lang F, et al. Eryptosis, a window to systemic disease. Cell Physiol Biochem. 2008;22:373–80.CrossRefPubMed Lang F, et al. Eryptosis, a window to systemic disease. Cell Physiol Biochem. 2008;22:373–80.CrossRefPubMed
19.
Zurück zum Zitat Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus. 2019;17:27–52.PubMedPubMedCentral Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus. 2019;17:27–52.PubMedPubMedCentral
20.
Zurück zum Zitat Jemaà M, et al. Stimulation of suicidal erythrocyte death by the CDC25 inhibitor NSC-95397. Cell Physiol Biochem. 2016;40:597–607.CrossRefPubMed Jemaà M, et al. Stimulation of suicidal erythrocyte death by the CDC25 inhibitor NSC-95397. Cell Physiol Biochem. 2016;40:597–607.CrossRefPubMed
21.
Zurück zum Zitat Fezai M, Slaymi C, Ben-Attia M, Lang F, Jemaà M. Purified lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest. Sci Rep. 2016;6:39288.CrossRefPubMedPubMedCentral Fezai M, Slaymi C, Ben-Attia M, Lang F, Jemaà M. Purified lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest. Sci Rep. 2016;6:39288.CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Jemaà M, Fezai M, Bissinger R, Lang F. Methods employed in cytofluorometric assessment of eryptosis, the suicidal erythrocyte death. Cell Physiol Biochem. 2017;43:431–44.CrossRefPubMed Jemaà M, Fezai M, Bissinger R, Lang F. Methods employed in cytofluorometric assessment of eryptosis, the suicidal erythrocyte death. Cell Physiol Biochem. 2017;43:431–44.CrossRefPubMed
23.
Zurück zum Zitat Lang E, Bissinger R, Gulbins E, Lang F. Ceramide in the regulation of eryptosis, the suicidal erythrocyte death. Apoptosis. 2015;20:758–67.CrossRefPubMed Lang E, Bissinger R, Gulbins E, Lang F. Ceramide in the regulation of eryptosis, the suicidal erythrocyte death. Apoptosis. 2015;20:758–67.CrossRefPubMed
24.
Zurück zum Zitat Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol. 2015;39:35–42.CrossRefPubMed Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol. 2015;39:35–42.CrossRefPubMed
25.
Zurück zum Zitat Lang F, Huber SM, Szabo I, Gulbins E. Plasma membrane ion channels in suicidal cell death. Arch Biochem Biophys. 2007;462:189–94.CrossRefPubMed Lang F, Huber SM, Szabo I, Gulbins E. Plasma membrane ion channels in suicidal cell death. Arch Biochem Biophys. 2007;462:189–94.CrossRefPubMed
26.
Zurück zum Zitat Lang F, Lang KS, Lang PA, Huber SM, Wieder T. Mechanisms and significance of eryptosis. Antioxid Redox Signal. 2006;8:1183–92.CrossRefPubMed Lang F, Lang KS, Lang PA, Huber SM, Wieder T. Mechanisms and significance of eryptosis. Antioxid Redox Signal. 2006;8:1183–92.CrossRefPubMed
27.
Zurück zum Zitat Lang E, Qadri SM, Lang F. Killing me softly—suicidal erythrocyte death. Int J Biochem Cell Biol. 2012;44:1236–43.CrossRefPubMed Lang E, Qadri SM, Lang F. Killing me softly—suicidal erythrocyte death. Int J Biochem Cell Biol. 2012;44:1236–43.CrossRefPubMed
28.
Zurück zum Zitat Lang F, Bissinger R, Abed M, Artunc F. Eryptosis—the neglected cause of anemia in end stage renal disease. Kidney Blood Press Res. 2017;42:749–60.CrossRefPubMed Lang F, Bissinger R, Abed M, Artunc F. Eryptosis—the neglected cause of anemia in end stage renal disease. Kidney Blood Press Res. 2017;42:749–60.CrossRefPubMed
29.
Zurück zum Zitat Al Mamun Bhuyan A, et al. Inhibition of suicidal erythrocyte death by volasertib. Cell Physiol Biochem. 2017;43:1472–86.CrossRefPubMed Al Mamun Bhuyan A, et al. Inhibition of suicidal erythrocyte death by volasertib. Cell Physiol Biochem. 2017;43:1472–86.CrossRefPubMed
31.
Zurück zum Zitat Gohda J, et al. BI-2536 and BI-6727, dual polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV‑1. Sci Rep. 2018;8:3521.CrossRefPubMedPubMedCentral Gohda J, et al. BI-2536 and BI-6727, dual polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV‑1. Sci Rep. 2018;8:3521.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Raab CA, Raab M, Becker S, Strebhardt K. Non-mitotic functions of polo-like kinases in cancer cells. Biochim Biophys Acta Rev Cancer. 2021;1875:188467.CrossRefPubMed Raab CA, Raab M, Becker S, Strebhardt K. Non-mitotic functions of polo-like kinases in cancer cells. Biochim Biophys Acta Rev Cancer. 2021;1875:188467.CrossRefPubMed
Metadaten
Titel
Polo-like kinase inhibitor BI2536 induces eryptosis
verfasst von
Dr. Mohamed Jemaà
Raja Mokdad Gargouri
Florian Lang
Publikationsdatum
30.09.2022
Verlag
Springer Vienna
Erschienen in
Wiener Medizinische Wochenschrift / Ausgabe 5-6/2023
Print ISSN: 0043-5341
Elektronische ISSN: 1563-258X
DOI
https://doi.org/10.1007/s10354-022-00966-7

Weitere Artikel der Ausgabe 5-6/2023

Wiener Medizinische Wochenschrift 5-6/2023 Zur Ausgabe