The microtubule depolymerizing agent CYT997 effectively kills acute myeloid leukemia cells via activation of caspases and inhibition of PI3K/Akt/mTOR pathway proteins

Chen,Xiaohui; Yang,Chunmei; Xu,Yanhua; Zhou,Hui; Liu,Hui; Qian,Wenbin

doi:10.3892/etm.2013.1161

The microtubule depolymerizing agent CYT997 effectively kills acute myeloid leukemia cells via activation of caspases and inhibition of PI3K/Akt/mTOR pathway proteins

Authors:
- Xiaohui Chen
- Chunmei Yang
- Yanhua Xu
- Hui Zhou
- Hui Liu
- Wenbin Qian
View Affiliations

Affiliations: Department of Hematology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China, Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: June 14, 2013 https://doi.org/10.3892/etm.2013.1161
Pages: 299-304

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

The orally active microtubule‑depolymerizing agent CYT997 is potently cytotoxic to a variety of tumors in vitro and in vivo. However, the effects of this agent on acute myeloid leukemia (AML) cells and its mechanisms are unknown. The present study demonstrated that CYT997 effectively inhibited the growth of AML cells in vitro. Treatment of AML cells with CYT997 resulted in G2/M phase cell cycle arrest, and induced apoptosis through the activation of extrinsic and intrinsic apoptotic pathways. Furthermore, CYT997 induced cell death in CD123+ leukemia cells and significantly reduced leukemia colony formation. CYT997 was also demonstrated to exert dual effects on the expression of PI3K/Akt and mechanistic target of rampamycin (mTOR) signaling pathway proteins. Therefore, CTY997, used alone or in combination with chemotherapy, may represent a promising approach for the treatment of AML.

View Figures

View References

1.	Steffen B, Müller-Tidow C, Schwäble J, Berdel WE and Serve H: The molecular pathogenesis of acute myeloid leukemia. Crit Rev Oncol Hematol. 56:195–221. 2005.PubMed/NCBI
2.	Kuppens IE: Current state of the art of new tubulin inhibitors in the clinic. Curr Clin Pharmacol. 1:57–70. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Rovini A, Savry A, Braguer D and Carré M: Microtubule-targeted agents: when mitochondria become essential to chemotherapy. Biochim Biophys Acta. 1807:679–688. 2011. View Article : Google Scholar : PubMed/NCBI
4.	Lysaght J, Verma NK, Maginn EN, et al: The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells. Int J Oncol. 42:239–246. 2013.PubMed/NCBI
5.	Petit I, Karajannis MA, Vincent L, et al: The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death. Blood. 111:1951–1961. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Greene LM, Kelly L, Onnis V, et al: STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells. J Pharmacol Exp Ther. 321:288–297. 2007. View Article : Google Scholar
7.	Burns CJ, Harte MF, Bu X, et al: Discovery of CYT997: a structurally novel orally active microtubule targeting agent. Bioorg Med Chem Lett. 19:4639–4642. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Burns CJ, Fantino E, Phillips ID, et al: CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo. Mol Cancer Ther. 8:3036–3045. 2009. View Article : Google Scholar : PubMed/NCBI
9.	Monaghan K, Khong T, Smith G and Spencer A: CYT997 causes apoptosis in human multiple myeloma. Invest New Drugs. 29:232–238. 2011. View Article : Google Scholar : PubMed/NCBI
10.	Burns CJ, Fantino E, Powell AK, et al: The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo. J Pharmacol Exp Ther. 339:799–806. 2011. View Article : Google Scholar : PubMed/NCBI
11.	Lickliter JD, Francesconi AB, Smith G, et al: Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent. Br J Cancer. 103:597–606. 2010. View Article : Google Scholar : PubMed/NCBI
12.	Burge M, Francesconi AB, Kotasek D, et al: Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent. Invest New Drugs. 31:126–135. 2013. View Article : Google Scholar : PubMed/NCBI
13.	Jordan CT, Upchurch D, Szilvassy SJ, et al: The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 14:1777–1784. 2000. View Article : Google Scholar : PubMed/NCBI
14.	Xu Q, Simpson SE, Scialla TJ, Bagg A and Carroll M: Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 102:972–980. 2003. View Article : Google Scholar : PubMed/NCBI
15.	Nathwani SM, Butler S, Fayne D, et al: Novel microtubule-targeting agents, pyrrolo-1, 5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells. Cancer Chemother Pharmacol. 66:585–596. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM and Pastan I: Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA. 84:265–269. 1987. View Article : Google Scholar : PubMed/NCBI
17.	Calligaris D, Verdier-Pinard P, Devred F, Villard C, Braguer D and Lafitte D: Microtubule targeting agents: from biophysics to proteomics. Cell Mol Life Sci. 67:1089–1104. 2010. View Article : Google Scholar : PubMed/NCBI
18.	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
19.	Meng H, Jin Y, Liu H, et al: SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. J Hematol Oncol. 6:182013. View Article : Google Scholar : PubMed/NCBI
20.	Min YH, Eom JI, Cheong JW, et al: Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 17:995–997. 2003. View Article : Google Scholar : PubMed/NCBI
21.	Récher C, Beyne-Rauzy O, Demur C, et al: Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 105:2527–2534. 2005.PubMed/NCBI
22.	Chapuis N, Tamburini J, Green AS, et al: Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res. 16:5424–5435. 2010. View Article : Google Scholar : PubMed/NCBI
23.	Gavet O and Pines J: Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis. Dev Cell. 18:533–543. 2010. View Article : Google Scholar : PubMed/NCBI
24.	Lu LX, Domingo-Sananes MR, Huzarska M, Novak B and Gould KL: Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches. Proc Natl Acad Sci USA. 109:9899–8904. 2012. View Article : Google Scholar : PubMed/NCBI