Open Access

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines

  • Authors:
    • Sara M. Ibrahim
    • Sherin Bakhashab
    • Asad M. Ilyas
    • Peter N. Pushparaj
    • Sajjad Karim
    • Jalaluddin A. Khan
    • Adel M. Abuzenadah
    • Adeel G. Chaudhary
    • Muhammed H. Al-Qahtani
    • Farid Ahmed
  • View Affiliations

  • Published online on: April 2, 2019     https://doi.org/10.3892/or.2019.7093
  • Pages: 3179-3188
  • Copyright: © Ibrahim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)‑resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP‑binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. Subsequently, the role of the mammalian target of rapamycin (mTOR) kinase inhibitor, WYE‑354, in sensitizing the K562/Adr200 and K562/Adr500 cell lines to Adr was evaluated. At sub‑cytotoxic concentrations, WYE‑354 increased Adr cytotoxicity in the K562/Adr200 and K562/Adr500 cells. WYE‑354 restored Adr sensitivity in the resistant cells by inhibiting ABCB1‑mediated substrate efflux, thereby leading to an accumulation of Adr, an increase in Adr‑mediated G2/M cell cycle arrest and the induction of apoptosis. Furthermore, WYE‑354 stimulated the ATPase activity of ABCB1, which was consistent with in silico predictions using a human ABCB1 mouse homology model, indicating that WYE‑354 is a potent substrate of ABCB1. WYE‑354 did not regulate the expression of ABCB1 at the concentrations used in the present study. These findings indicate that WYE‑354 may be a competitive inhibitor of ABCB1‑mediated efflux and a potential candidate in combination with standard chemotherapy for overcoming MDR. Further clinical investigations are warranted to validate this combination in vivo.
View Figures
View References

Related Articles

Journal Cover

June-2019
Volume 41 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
APA
Ibrahim, S.M., Bakhashab, S., Ilyas, A.M., Pushparaj, P.N., Karim, S., Khan, J.A. ... Ahmed, F. (2019). WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines. Oncology Reports, 41, 3179-3188. https://doi.org/10.3892/or.2019.7093
MLA
Ibrahim, S. M., Bakhashab, S., Ilyas, A. M., Pushparaj, P. N., Karim, S., Khan, J. A., Abuzenadah, A. M., Chaudhary, A. G., Al-Qahtani, M. H., Ahmed, F."WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines". Oncology Reports 41.6 (2019): 3179-3188.
Chicago
Ibrahim, S. M., Bakhashab, S., Ilyas, A. M., Pushparaj, P. N., Karim, S., Khan, J. A., Abuzenadah, A. M., Chaudhary, A. G., Al-Qahtani, M. H., Ahmed, F."WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines". Oncology Reports 41, no. 6 (2019): 3179-3188. https://doi.org/10.3892/or.2019.7093