Pharmacological agents with inherent anti-autophagic activity improve the cytotoxicity of imatinib

Crowley,Lisa C.; O'Donovan,Tracey R.; Nyhan,Michelle J.; McKenna,Sharon L.

doi:10.3892/or.2013.2377

Pharmacological agents with inherent anti-autophagic activity improve the cytotoxicity of imatinib

Authors:
- Lisa C. Crowley
- Tracey R. O'Donovan
- Michelle J. Nyhan
- Sharon L. McKenna
View Affiliations

Affiliations: Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland
Published online on: April 3, 2013 https://doi.org/10.3892/or.2013.2377
Pages: 2261-2268

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

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

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) remains a limitation to the treatment of chronic myeloid leukaemia (CML), due in part, to the induction of autophagy. We examined whether disruption of autophagy with the pharmacological agents, brefeldin A, vincristine and chloroquine, improves the cytotoxicity of imatinib. In K562 CML cells, all drugs tested, in combination with imatinib impaired the expression or cellular distribution of LC3 and Beclin 1 (autophagy markers) and reduced the recovery of cells following drug withdrawal. The combination of imatinib and an agent that impedes autophagy demonstrates impressive potential as a more curative regime for CML.

View Figures

View References

1	Nowell PC and Hungerford DA: A minute chromosome in human chronic granulocyte leukeamia. Science. 132:1497–1501. 1960.
2	Melo JV: The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 88:2375–2384. 1996.PubMed/NCBI
3	Calabretta B and Perrotti D: The biology of CML blast crisis. Blood. 103:4010–4022. 2004. View Article : Google Scholar : PubMed/NCBI
4	Quentmeier H, Eberth S, Romani J, Zaborski M and Drexler HG: BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance. J Hematol Oncol. 4:62011. View Article : Google Scholar : PubMed/NCBI
5	Cortes J, O’Brien S and Kantarjian H: Discontinuation of imatinib therapy after achieving a molecular response. Blood. 104:2204–2205. 2004. View Article : Google Scholar : PubMed/NCBI
6	Crowley LC, Elzinga BM, O’Sullivan GC and McKenna SL: Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment. Am J Hematol. 86:38–47. 2011. View Article : Google Scholar : PubMed/NCBI
7	Bellodi C, Lidonnici MR, Hamilton A, et al: Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest. 119:1109–1123. 2009. View Article : Google Scholar
8	Mizushima N: Autophagy: process and function. Genes Dev. 21:2861–2873. 2007. View Article : Google Scholar
9	Degtyarev M, De Maziere A, Orr C, et al: Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol. 183:101–116. 2008. View Article : Google Scholar : PubMed/NCBI
10	Holyoakes T; Medical Research Council. Research Portofolio: A randomised phase II trial of IM versus HCQ/IM for patients with CML in MCyR with residual disease by Q-PCR. http://www.mrc.ac.uk/ResearchPortfolio/Grant/Record.htm?GrantRef=G0900882&CaseId=15301.
11	Eskelinen EL, Prescott AR, Cooper J, et al: Inhibition of autophagy in mitotic animal cells. Traffic. 3:878–893. 2002. View Article : Google Scholar : PubMed/NCBI
12	Groth-Pedersen L, Ostenfeld MS, Hoyer-Hansen M, Nylandsted J and Jaattela M: Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res. 67:2217–2225. 2007. View Article : Google Scholar : PubMed/NCBI
13	Vetterlein M, Niapir M, Ellinger A, Neumüller J and Pavelka M: Brefeldin A-regulated retrograde transport into the endoplasmic reticulum of internalised wheat germ agglutinin. Histochem Cell Biol. 120:121–128. 2003. View Article : Google Scholar : PubMed/NCBI
14	Nishida Y, Arakawa S, Fujitani K, et al: Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature. 461:654–658. 2009. View Article : Google Scholar : PubMed/NCBI
15	Aguayo A and Couban S: State-of-the-art in the management of chronic myelogenous leukemia in the era of the tyrosine kinase inhibitors: evolutionary trends in diagnosis, monitoring and treatment. Leuk Lymphoma. 50(Suppl 2): 1–8. 2009. View Article : Google Scholar
16	O’Brien SG, Guilhot F, Goldman JM, et al: International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib (IM). (ASH Annual Meeting Abstracts). Blood. 112:1862008.
17	Amaravadi RK, Lippincott-Schwartz J, Yin X-M, et al: Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 17:654–666. 2011. View Article : Google Scholar : PubMed/NCBI
18	Lassen U, Kristjansen PE, Osterlind K, et al: Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up. Ann Oncol. 7:365–371. 1996.PubMed/NCBI
19	Pommepuy I, Terro F, Petit B, et al: Brefeldin A induces apoptosis and cell cycle blockade in glioblastoma cell lines. Oncology. 64:459–467. 2003. View Article : Google Scholar : PubMed/NCBI
20	Chapman JR, Tazaki H, Mallouh C and Konno S: Brefeldin A-induced apoptosis in prostatic cancer DU-145 cells: a possible p53-independent death pathway. BJU Int. 83:703–708. 1999. View Article : Google Scholar : PubMed/NCBI
21	Larsson DE, Wickström M, Hassan S, OBerg K and Granberg DAN: The cytotoxic agents NSC-95397, brefeldin A, bortezomib and sanguinarine induce apoptosis in neuroendocrine tumors in vitro. Anticancer Res. 30:149–156. 2010.PubMed/NCBI
22	Fox BM, Vroman JA, Fanwick PE and Cushman M: Preparation and evaluation of sulfide derivatives of the antibiotic brefeldin A as potential prodrug candidates with enhanced aqueous solubilities. J Med Chem. 44:3915–3924. 2001. View Article : Google Scholar : PubMed/NCBI
23	Phillips LR, Wolfe TL, Malspeis L and Supko JG: Analysis of brefeldin A and the prodrug breflate in plasma by gas chromatography with mass selective detection. J Pharm Biomed Anal. 16:1301–1309. 1998. View Article : Google Scholar : PubMed/NCBI
24	Anadu NO, Davisson VJ and Cushman M: Synthesis and anticancer activity of brefeldin A ester derivatives. J Med Chem. 49:3897–3905. 2006. View Article : Google Scholar : PubMed/NCBI
25	Kamitsuji Y, Kuroda J, Kimura S, et al: The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 15:1712–1722. 2008. View Article : Google Scholar : PubMed/NCBI
26	Carew JS, Nawrocki ST, Kahue CN, et al: Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood. 110:313–322. 2007. View Article : Google Scholar : PubMed/NCBI
27	Qadir MA, Kwok B, Dragowska WH, et al: Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat. 112:389–403. 2008. View Article : Google Scholar
28	Ullen A, Farnebo M, Thyrell L, et al: Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro. Int J Oncol. 37:15–20. 2010. View Article : Google Scholar
29	O’Donovan TR, O’Sullivan GC and McKenna SL: Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy. 7:509–524. 2011.PubMed/NCBI
30	Mortensen M, Soilleux EJ, Djordjevic G, et al: The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med. 208:455–467. 2011. View Article : Google Scholar : PubMed/NCBI