Please use this identifier to cite or link to this item:
https://hdl.handle.net/11147/5864
Title: | A molecular and biophysical comparison of macromolecular changes in imatinib-sensitive and imatinib-resistant K562 cells exposed to ponatinib | Authors: | Kartal Yandım, Melis Ceylan, Çağatay Elmas, Efe Baran, Yusuf |
Keywords: | Chronic myeloid leukemia Fourier transform infrared spectroscopy FTIR Imatinib Multidrug resistance Ponatinib |
Publisher: | SAGE Publications Inc. | Source: | Kartal Yandım, M., Ceylan, Ç., Elmas, E., and Baran, Y. (2016). A molecular and biophysical comparison of macromolecular changes in imatinib-sensitive and imatinib-resistant K562 cells exposed to ponatinib. Tumor Biology, 37(2), 2365-2378. doi:10.1007/s13277-015-4015-9 | Abstract: | Chronic myeloid leukemia (CML) is a type of hematological malignancy that is characterized by the generation of Philadelphia chromosome encoding BCR/ABL oncoprotein. Tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, are used for the frontline therapy of CML. Development of resistance against these TKIs in the patients bearing T315I mutation is a major obstacle in CML therapy. Ponatinib, the third-generation TKI, is novel drug that is effective even in CML patients with T315I mutation. The exact mechanism of ponatinib in CML has been still unknown. In this study, we aimed to determine the potential mechanisms and structural metabolic changes activated by ponatinib treatment in imatinib-sensitive K562 human CML cell lines and 3 μM-imatinib-resistant K562/IMA3 CML cell lines generated at our lab. Apoptotic and antiproliferative effects of ponatinib on imatinib-sensitive and 3 μM-imatinib-resistant K562/IMA3 CML cells were determined by proliferation and apoptosis assays. Additionally, the effects of ponatinib on macromolecules and lipid profiles were also analyzed using Fourier transform infrared spectroscopy (FTIR). Our results revealed that ponatinib inhibited cell proliferation and induced apoptosis as determined by loss of mitochondrial membrane potential, increased caspase-3 enzyme activity, and transfer of phosphatidylserine to the plasma membrane in both K562 and K562/IMA-3 cells. Furthermore, cell cycle analyses revealed that ponatinib arrested K562 and K562/IMA-3 cells at G1 phase. Moreover, ponatinib treatment created a more ordered nucleic acid structure in the resistant cells. Although the lipid to protein ratio increased in imatinib-sensitive K562 cells with a little decrease in the K562/IMA-3 cells, ponatinib treatment indicated significant changes in the lipid composition such as a significant increase in the cellular cholesterol amounts much more in the K562/IMA-3 cells than the sensitive counterparts. Unsaturation in lipids was higher in the resistant cells; however, increases in lipids without phosphate and the number of acyl chains were much higher in the K562 cells. Taken together, all these results showed powerful antiproliferative and apoptotic effects of ponatinib in both imatinib-sensitive and imatinib-resistant CML cells in a dose-dependent manner, and hence, the use of ponatinib for the treatment of TKI-resistant CML patients may be an effective treatment approach in the clinic. More importantly, these results showed that FTIR spectroscopy can detect drug-induced physiological changes in cancer drug resistance. | URI: | https://doi.org/10.1007/s13277-015-4015-9 http://hdl.handle.net/11147/5864 |
ISSN: | 1423-0380 1010-4283 |
Appears in Collections: | Food Engineering / Gıda Mühendisliği Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection |
Show full item record
CORE Recommender
SCOPUSTM
Citations
6
checked on Sep 1, 2024
WEB OF SCIENCETM
Citations
6
checked on Aug 24, 2024
Page view(s)
222
checked on Sep 2, 2024
Download(s)
434
checked on Sep 2, 2024
Google ScholarTM
Check
Altmetric
Items in GCRIS Repository are protected by copyright, with all rights reserved, unless otherwise indicated.