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.

References

1 

Gottesman MM: Mechanisms of cancer drug resistance. Annu Rev Med. 53:615–627. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Shaffer BC, Gillet JP, Patel C, Baer MR, Bates SE and Gottesman MM: Drug resistance: Still a daunting challenge to the successful treatment of AML. Drug Resist Updat. 15:62–69. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Parkin B, Ouillette P, Li Y, Keller J, Lam C, Roulston D, Li C, Shedden K and Malek SN: Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood. 121:369–377. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Löscher W and Potschka H: Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 76:22–76. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Mohammad IS, He W and Yin L: Understanding of human ATP binding cassette superfamily and novel multidrug resistance modulators to overcome MDR. Biomed Pharmacother. 100:335–348. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Dean M, Rzhetsky A and Allikmets R: The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11:1156–1166. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Kathawala RJ, Gupta P, Ashby CR Jr and Chen ZS: The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist Updat. 18:1–17. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Binkhathlan Z and Lavasanifar A: P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: Current status and future perspectives. Curr Cancer Drug Targets. 13:326–346. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Yang K, Chen Y, To KK, Wang F, Li D, Chen L and Fu L: Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo. Exp Mol Med. 49:e3032017. View Article : Google Scholar : PubMed/NCBI

10 

Zhang YK, Zhang GN, Wang YJ, Patel BA, Talele TT, Yang DH and Chen ZS: Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters. Sci Rep. 6:256942016. View Article : Google Scholar : PubMed/NCBI

11 

Qiu JG, Zhang YJ, Li Y, Zhao JM, Zhang WJ, Jiang QW, Mei XL, Xue YQ, Qin WM, Yang Y, et al: Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter. Oncotarget. 6:15494–15509. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Li J, Kumar P, Anreddy N, Zhang YK, Wang YJ, Chen Y, Talele TT, Gupta K, Trombetta LD and Chen ZS: Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: In vitro and in vivo studies. Oncotarget. 8:93785–93799. 2017.PubMed/NCBI

13 

Dos Santos C, Récher C, Demur C and Payrastre B: The PI3K/Akt/mTOR pathway: A new therapeutic target in the treatment of acute myeloid leukemia. Bull Cancer. 93:445–447. 2006.(In French). PubMed/NCBI

14 

Dinner S and Platanias LC: Targeting the mTOR Pathway in Leukemia. J Cell Biochem. 117:1745–1752. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, et al RECORD-1 Study Group, : Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer. 116:4256–4265. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Hudes GR, Berkenblit A, Feingold J, Atkins MB, Rini BI and Dutcher J: Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma. Semin Oncol. 36 (Suppl 3):S26–S36. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Park S, Chapuis N, Saint Marcoux F, Recher C, Prebet T, Chevallier P, Cahn JY, Leguay T, Bories P, Witz F, et al GOELAMS (Groupe Ouest Est d'Etude des Leucémies aiguës et Autres Maladies du Sang), : A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia. 27:1479–1486. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ and Koeffler HP: Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia. 21:333–339. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Grünwald V, DeGraffenried L, Russel D, Friedrichs WE, Ray RB and Hidalgo M: Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res. 62:6141–6145. 2002.PubMed/NCBI

20 

Wang Z, Huang Y and Zhang J: Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy. Cell Mol Biol Lett. 19:233–242. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, et al: The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 166:213–223. 2004. View Article : Google Scholar : PubMed/NCBI

22 

Sun SY: mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett. 340:1–8. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ, et al: Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 69:6232–6240. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Wang L, Zhu YR, Wang S and Zhao S: Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo. Tumour Biol. 37:11743–11752. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Weber H, Leal P, Stein S, Kunkel H, García P, Bizama C, Espinoza JA, Riquelme I, Nervi B, Araya JC, et al: Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice. Oncotarget. 6:31877–31888. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Salvia AM, Cuviello F, Coluzzi S, Nuccorini R, Attolico I, Pascale SP, Bisaccia F, Pizzuti M and Ostuni A: Expression of some ATP-binding cassette transporters in acute myeloid leukemia. Hematol Rep. 9:74062017. View Article : Google Scholar : PubMed/NCBI

28 

Liu B, Li LJ, Gong X, Zhang W, Zhang H and Zhao L: Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia. Oncol Lett. 15:6671–6677. 2018.PubMed/NCBI

29 

Beretta GL, Cassinelli G, Pennati M, Zuco V and Gatt L: Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents. Eur J Med Chem. 142:271–289. 2017. View Article : Google Scholar : PubMed/NCBI

30 

Martelli AM, Evangelisti C, Chiarini F and McCubrey JA: The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 1:89–103. 2010.PubMed/NCBI

31 

Tabe Y, Tafuri A, Sekihara K, Yang H and Konopleva M: Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia. Expert Opin Ther Targets. 21:705–714. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Ying L, Zu-An Z, Qing-Hua L, Qing-Yan K, Lei L, Tao C and Yong-Ping W: RAD001 can reverse drug resistance of SGC7901/DDP cells. Tumour Biol. 35:9171–9177. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Ma Q, Chang Z, Wang W and Wang B: Rapamycin-mediated mTOR inhibition reverses drug resistance to adriamycin in colon cancer cells. Hepatogastroenterology. 62:880–886. 2015.PubMed/NCBI

34 

Deng L, Jiang L, Lin XH, Tseng KF, Liu Y, Zhang X, Dong RH, Lu ZG and Wang XJ: The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Acta Pharmacol Sin. 38:382–391. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Lee JS, Paull K, Alvarez M, Hose C, Monks A, Grever M, Fojo AT and Bates SE: Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 46:627–638. 1994.PubMed/NCBI

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
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