Tags

Type your tag names separated by a space and hit enter

Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines.
Sci Rep 2020; 10(1):959SR

Abstract

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to overcome tyrosine kinase inhibitor (TKI) resistance in epithelial growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) cells in vivo and in vitro. However, little is known about the putative induction of non-apoptotic cell death pathways by statins. We investigated the effects of pitavastatin and fluvastatin alone or in combination with erlotinib in three NSCLC cell lines and examined the activation of different cell death pathways. We assessed apoptosis via fluorometric caspase assay and poly (ADP-ribose) polymerase 1 (PARP) cleavage. Furthermore, annexinV/propidium iodide (PI) flow cytometry was performed. Small molecule inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD), necrostatin 1 (Nec1), ferrostatin 1 (Fer1), Ac-Lys-Lys-Norleucinal (Calp1) were used to characterise cell death pathway(s) putatively (co-)activated by pitavastatin/erlotinib co-treatment. Synergism was calculated by additivity and isobolographic analyses. Pitavastatin and fluvastatin induced cell death in EGFR TKI resistant NSCLC cells lines A549, Calu6 and H1993 as shown by caspase 3 activation and PARP cleavage. Co-treatment of cells with pitavastatin and the EGFR TKI erlotinib resulted in synergistically enhanced cytotoxicity compared to pitavastatin monotherapy. Flow cytometry indicated the induction of alternative regulated cell death pathways. However, only co-treatment with mevalonic acid (Mev) or the pan-caspase inhibitor zVAD could restore cell viability. The results show that cytotoxicity mediated by statin/erlotinib co-treatment is synergistic and can overcome erlotinib resistance in K-ras mutated NSCLC and relies only on apoptosis.

Authors+Show Affiliations

Anna Spiegel Research Facility, Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.Anna Spiegel Research Facility, Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Department of Medical Biochemistry, School of Medicine, Koc University, Istanbul, Turkey. Koc University Research Center for Translational Research (KUTTAM), Istanbul, Turkey.Anna Spiegel Research Facility, Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.Anna Spiegel Research Facility, Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. christoph.minichsdorfer@meduniwien.ac.at.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31969600

Citation

Otahal, Alexander, et al. "Delineation of Cell Death Mechanisms Induced By Synergistic Effects of Statins and Erlotinib in Non-small Cell Lung Cancer Cell (NSCLC) Lines." Scientific Reports, vol. 10, no. 1, 2020, p. 959.
Otahal A, Aydemir D, Tomasich E, et al. Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines. Sci Rep. 2020;10(1):959.
Otahal, A., Aydemir, D., Tomasich, E., & Minichsdorfer, C. (2020). Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines. Scientific Reports, 10(1), p. 959. doi:10.1038/s41598-020-57707-2.
Otahal A, et al. Delineation of Cell Death Mechanisms Induced By Synergistic Effects of Statins and Erlotinib in Non-small Cell Lung Cancer Cell (NSCLC) Lines. Sci Rep. 2020 Jan 22;10(1):959. PubMed PMID: 31969600.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines. AU - Otahal,Alexander, AU - Aydemir,Duygu, AU - Tomasich,Erwin, AU - Minichsdorfer,Christoph, Y1 - 2020/01/22/ PY - 2019/01/10/received PY - 2020/01/02/accepted PY - 2020/1/24/entrez PY - 2020/1/24/pubmed PY - 2020/1/24/medline SP - 959 EP - 959 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to overcome tyrosine kinase inhibitor (TKI) resistance in epithelial growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) cells in vivo and in vitro. However, little is known about the putative induction of non-apoptotic cell death pathways by statins. We investigated the effects of pitavastatin and fluvastatin alone or in combination with erlotinib in three NSCLC cell lines and examined the activation of different cell death pathways. We assessed apoptosis via fluorometric caspase assay and poly (ADP-ribose) polymerase 1 (PARP) cleavage. Furthermore, annexinV/propidium iodide (PI) flow cytometry was performed. Small molecule inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD), necrostatin 1 (Nec1), ferrostatin 1 (Fer1), Ac-Lys-Lys-Norleucinal (Calp1) were used to characterise cell death pathway(s) putatively (co-)activated by pitavastatin/erlotinib co-treatment. Synergism was calculated by additivity and isobolographic analyses. Pitavastatin and fluvastatin induced cell death in EGFR TKI resistant NSCLC cells lines A549, Calu6 and H1993 as shown by caspase 3 activation and PARP cleavage. Co-treatment of cells with pitavastatin and the EGFR TKI erlotinib resulted in synergistically enhanced cytotoxicity compared to pitavastatin monotherapy. Flow cytometry indicated the induction of alternative regulated cell death pathways. However, only co-treatment with mevalonic acid (Mev) or the pan-caspase inhibitor zVAD could restore cell viability. The results show that cytotoxicity mediated by statin/erlotinib co-treatment is synergistic and can overcome erlotinib resistance in K-ras mutated NSCLC and relies only on apoptosis. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/31969600/Delineation_of_cell_death_mechanisms_induced_by_synergistic_effects_of_statins_and_erlotinib_in_non-small_cell_lung_cancer_cell_(NSCLC)_lines L2 - http://dx.doi.org/10.1038/s41598-020-57707-2 DB - PRIME DP - Unbound Medicine ER -