Idelalisib induces G1 arrest and apoptosis in chronic myeloid leukemia K562 cells

Chen,Yali; Zhou,Qianxiang; Zhang,Lei; Wang,Ran; Jin,Meihua; Qiu,Yuling; Kong,Dexin

doi:10.3892/or.2016.5176

Idelalisib induces G1 arrest and apoptosis in chronic myeloid leukemia K562 cells

Authors:
- Yali Chen
- Qianxiang Zhou
- Lei Zhang
- Ran Wang
- Meihua Jin
- Yuling Qiu
- Dexin Kong
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Affiliations: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Heping, Tianjin 300070, P.R. China
Published online on: October 17, 2016 https://doi.org/10.3892/or.2016.5176
Pages: 3643-3650

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Abstract

Increasing resistance of imatinib, a BCR-ABL tyrosine kinase inhibitor, hinders its use in the therapy of chronic myeloid leukemia (CML). The PI3K pathway is known to be closely involved in BCR-ABL transformation and the tumorigenesis of CML, suggesting that PI3K may be a potential target for CML therapy. Idelalisib, a specific inhibitor of PI3K p110δ, has been approved for the treatment of chronic lymphocytic leukemia (CLL). However, the antileukemia effect of idelalisib on CML remains unknown. In the present study, the antileukemia activity of idelalisib alone or in combination with imatinib was investigated by use of K562 cells. Idelalisib inhibited K562 proliferation in a dose-dependent manner. G1 arrest was induced, in which upregulation of p27 and p21, as well as downregulation of cyclin D1 and p-pRb, may be involved. Furthermore, idelalisib induced apoptosis in the K562 cells, with increased expression of pro-apoptotic molecules such as Bad and Bax, cleavage of caspase-9, -8 and -3, and PARP, in contrast to downregulation of anti-apoptotic protein Bcl-2. Combination of idelalisib with imatinib led to a synergistic antiproliferative effect on K562 cells, together with enhanced activity of G1 arrest and apoptosis induction. In conclusion, idelalisib exhibited in vitro antitumor activity on CML K562 cells alone or in combination with imatinib, suggesting potential application in CML therapy.

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1	Maru Y: Molecular biology of chronic myeloid leukemia. Cancer Sci. 103:1601–1610. 2012. View Article : Google Scholar : PubMed/NCBI
2	Holyoake TL and Helgason GV: Do we need more drugs for chronic myeloid leukemia? Immunol Rev. 263:106–123. 2015. View Article : Google Scholar : PubMed/NCBI
3	Rangatia J and Bonnet D: Transient or long-term silencing of BCR-ABL alone induces cell cycle and proliferation arrest, apoptosis and differentiation. Leukemia. 20:68–76. 2006. View Article : Google Scholar : PubMed/NCBI
4	Chereda B and Melo JV: Natural course and biology of CML. Ann Hematol. 94:(Suppl 2). S107–S121. 2015. View Article : Google Scholar : PubMed/NCBI
5	Larson RA: Is there a best TKI for chronic phase CML? Blood. 126:2370–2375. 2015. View Article : Google Scholar : PubMed/NCBI
6	Liu N, Zang S, Liu Y, Wang Y, Li W, Liu Q, Ji M, Ma D and Ji C: FZD7 regulates BMSC-mediated protection of CML cells. Oncotarget. 7:6175–6187. 2016.PubMed/NCBI
7	Brown JR: Idelalisib has CLL on the run! Blood. 126:2656–2657. 2015. View Article : Google Scholar : PubMed/NCBI
8	Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, et al: Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 123:3390–3397. 2014. View Article : Google Scholar : PubMed/NCBI
9	Morabito F, Gentile M, Seymour JF and Polliack A: Ibrutinib, idelalisib and obinutuzumab for the treatment of patients with chronic lymphocytic leukemia: Three new arrows aiming at the target. Leuk Lymphoma. 56:3250–3256. 2015. View Article : Google Scholar : PubMed/NCBI
10	Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM and Fruman DA: Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL⁺ leukemia cells. J Clin Invest. 118:3038–3050. 2008. View Article : Google Scholar : PubMed/NCBI
11	Byrd JC, Woyach JA and Johnson AJ: Translating PI3K-delta inhibitors to the clinic in chronic lymphocytic leukemia: The story of CAL-101 (GS1101). Am Soc Clin Oncol Educ Book. 2012.691–694. 2012.doi: 10.14694/EdBook_AM.2012.32.691. PubMed/NCBI
12	Chen X, Tang SA, Lee E, Qiu Y, Wang R, Duan HQ, Dan S, Jin M and Kong D: IVSE, isolated from Inula japonica, suppresses LPS-induced NO production via NF-κB and MAPK inactivation in RAW264.7 cells. Life Sci. 124:8–15. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Tang SA, Wang R, Qiu Y, Jin M and Kong D: Inhibitory effects of JEUD-38, a new sesquiterpene lactone from Inula japonica thunb, on LPS-induced iNOS expression in RAW264.7 cells. Inflammation. 38:941–948. 2015. View Article : Google Scholar : PubMed/NCBI
14	Liu Y, Zhang X, Wang J, Yang J and Tan WF: JNK is required for maintaining the tumor-initiating cell-like properties of acquired chemoresistant human cancer cells. Acta Pharmacol Sin. 36:1099–1106. 2015. View Article : Google Scholar : PubMed/NCBI
15	Tang SA, Zhou Q, Guo WZ, Qiu Y, Wang R, Jin M, Zhang W, Li K, Yamori T, Dan S, et al: In vitro antitumor activity of stellettin B, a triterpene from marine sponge Jaspis stellifera, on human glioblastoma cancer SF295 cells. Mar Drugs. 12:4200–4213. 2014. View Article : Google Scholar : PubMed/NCBI
16	Wang Y, Liu J, Qiu Y, Jin M, Chen X, Fan G, Wang R and Kong D: ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells. Oncotarget. 7:19897–19909. 2016.PubMed/NCBI
17	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
18	Radujkovic A, Luft T, Dreger P, Ho AD, Zeller W Jens, Fruehauf S and Topaly J: In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia. Cancer Chemother Pharmacol. 74:427–432. 2014. View Article : Google Scholar : PubMed/NCBI
19	Kong D, Yamori T, Yamazaki K and Dan S: In vitro multifaceted activities of a specific group of novel phosphatidylinositol 3-kinase inhibitors on hotspot mutant PIK3CA. Invest New Drugs. 32:1134–1143. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhao W, Guo W, Zhou Q, Ma SN, Wang R, Qiu Y, Jin M, Duan HQ and Kong D: In vitro antimetastatic effect of phosphatidylinositol 3-kinase inhibitor ZSTK474 on prostate cancer PC3 cells. Int J Mol Sci. 14:13577–13591. 2013. View Article : Google Scholar : PubMed/NCBI
21	Kusakawa S, Yasuda S, Kuroda T, Kawamata S and Sato Y: Ultra-sensitive detection of tumorigenic cellular impurities in human cell-processed therapeutic products by digital analysis of soft agar colony formation. Sci Rep. 5:17892–17902. 2015. View Article : Google Scholar : PubMed/NCBI
22	Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA and McCubrey JA: Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia. 17:590–603. 2003. View Article : Google Scholar : PubMed/NCBI
23	Neri LM, Cani A, Martelli AM, Simioni C, Junghanss C, Tabellini G, Ricci F, Tazzari PL, Pagliaro P, McCubrey JA, et al: Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia. 28:739–748. 2014. View Article : Google Scholar : PubMed/NCBI
24	Fruman DA and Rommel C: PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov. 13:140–156. 2014. View Article : Google Scholar : PubMed/NCBI
25	Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE and McCubrey JA: JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 18:189–218. 2004. View Article : Google Scholar : PubMed/NCBI
26	Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N, et al: Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood. 106:1063–1066. 2005. View Article : Google Scholar : PubMed/NCBI
27	Mayer IA and Arteaga CL: The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 67:11–28. 2016. View Article : Google Scholar : PubMed/NCBI
28	Sui H, Pan SF, Feng Y, Jin BH, Liu X, Zhou LH, Hou FG, Wang WH, Fu XL, Han ZF, et al: Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway. BMC Complement Altern Med. 14:279–288. 2014. View Article : Google Scholar : PubMed/NCBI
29	Faes S and Dormond O: PI3K and AKT: Unfaithful partners in cancer. Int J Mol Sci. 16:21138–21152. 2015. View Article : Google Scholar : PubMed/NCBI
30	Warfel NA and Kraft AS: PIM kinase (and Akt) biology and signaling in tumors. Pharmacol Ther. 151:41–49. 2015. View Article : Google Scholar : PubMed/NCBI
31	Radogna F, Dicato M and Diederich M: Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem Pharmacol. 94:1–11. 2015. View Article : Google Scholar : PubMed/NCBI
32	Green DR and Llambi F: Cell death signaling. Cold Spring Harb Perspect Biol. 7:a0060802015. View Article : Google Scholar : PubMed/NCBI
33	Ren C, Ren T, Yang K, Wang S, Bao X, Zhang F and Guo W: Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway. J Exp Clin Cancer Res. 35:44–57. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zhang X, Tang N, Hadden TJ and Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 1813:1978–1986. 2011. View Article : Google Scholar : PubMed/NCBI