Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines

Journal of Biomedical Science

Christian Berthou⁴  Laurent Meijer¹  Hervé Galons²  Nassima Oumata¹  Mélina Blairvacq⁵  Samuel Troadec³ 

[1] ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, Roscoff, France;Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes UMR-S 1022 Inserm, 4 avenue de l’Observatoire, Paris, France;Current address: Institut Universitaire Technologique, Département de Génie Biologique, Brest, France;Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, Brest Cedex, 29609, France;“Protein Phosphorylation and Human Diseases” Group, CNRS, USR3151, Station Biologique, Roscoff, France

关键词: Apoptotic signalling;    Apoptosis;    Cell cycle;    Chronic myeloid leukemia;    Cyclin-dependent kinases inhibitors;   

Others  :  1219599
DOI  :  10.1186/s12929-015-0163-x

 received in 2015-03-10, accepted in 2015-07-02,  发布年份 2015

【 摘 要 】

Background

Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.

Results

In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and –resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.

Conclusions

These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

【 授权许可】

   
2015 Troadec et al.

【 图 表 】

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【 参考文献 】

• [1]Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960; 25:85-109.
• [2]Melo JV, Chuah C. Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematology Am Soc Hematol Educ Program. 2008;427–435.
• [3]Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al.. Clinical resistance to sti-571 cancer therapy caused by bcr-abl gene mutation or amplification. Science. 2001; 293:876-880.
• [4]Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al.. Mdr1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003; 101:2368-2373.
• [5]Konig H, Holtz M, Modi H, Manley P, Holyoake TL, Forman SJ et al.. Enhanced bcr-abl kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in cmL progenitors. Leukemia. 2008; 22:748-755.
• [6]Mahon FX, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F et al.. Evidence that resistance to nilotinib may be due to bcr-abl, pgp, or src kinase overexpression. Cancer Res. 2008; 68:9809-9816.
• [7]Sattler M, Golam Mohi M, Pride YB, Quinnan LR, Malouf NA, Podar K et al.. Critical role for gab2 in transformation by bcr/abl. Cancer Cell. 2002; 1:479-492.
• [8]Sattler M, Pride YB, Quinnan LR, Verma S, Malouf NA, Husson H et al.. Differential expression and signaling of cbl and cbl-b in bcr/abl transformed cells. Oncogene. 2002; 21:1423-1433.
• [9]Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol. 1997; 13:261-291.
• [10]Hartwell LH, Kastan MB. Cell cycle control and cancer. Science. 1994; 266:1821-1828.
• [11]Fischer PM, Gianella-Borradori A. Recent progress in the discovery and development of cyclin-dependent kinase inhibitors. Expert Opin Investig Drugs. 2005; 14:457-477.
• [12]Malumbres M, Barbacid M. Cell cycle kinases in cancer. Curr Opin Genet Dev. 2007; 17:60-65.
• [13]Meijer L, Raymond E. Roscovitine and other purines as kinase inhibitors. from starfish oocytes to clinical trials. Acc Chem Res. 2003; 36:417-425.
• [14]Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N et al.. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997; 243:527-536.
• [15]Guzi T. Cyc-202 cyclacel. Curr Opin Investig Drugs. 2004; 5:1311-1318.
• [16]Bach S, Knockaert M, Reinhardt J, Lozach O, Schmitt S, Baratte B et al.. Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem. 2005; 280:31208-31219.
• [17]McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM et al.. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor cyc202 (r-roscovitine). Int J Cancer. 2002; 102:463-468.
• [18]Benson C, White J, De Bono J, O’Donnell A, Raynaud F, Cruickshank C et al.. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (cyc202; r-roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007; 96:29-37.
• [19]Oumata N, Bettayeb K, Ferandin Y, Demange L, Lopez-Giral A, Goddard ML et al.. Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1. J Med Chem. 2008; 51:5229-5242.
• [20]Bettayeb K, Oumata N, Echalier A, Ferandin Y, Endicott JA, Galons H et al.. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene. 2008; 27:5797-5807.
• [21]Delehouzé C, Godl K, Loaëc N, Bruyère C, Desban N, Oumata N et al.. Cdk/ck1 inhibitors roscovitine and cr8 downregulate amplified mycn in neuroblastoma cells. Oncogene. 2014; 33:5675-5687.
• [22]Meijer L, Bettayeb K, Galons H. Roscovitine (cyc202, seliciclib). In: Smith P, Yue E, editors. Monographs on enzyme inhibitors. CRC Press, Taylor & Francis, 2006;187–226.
• [23]Iseki H, Ko TC, Xue XY, Seapan A, Hellmich MR, Townsend CM. Cyclin-dependent kinase inhibitors block proliferation of human gastric cancer cells. Surgery. 1997; 122:187-195.
• [24]Sherr CJ. The pezcoller lecture: cancer cell cycles revisited. Cancer Res. 2000; 60:3689-3695.
• [25]Blagosklonny MV, Pardee AB. Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res. 2001; 61:4301-4305.
• [26]MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A et al.. Seliciclib (cyc202, r-roscovitine) induces cell death in multiple myeloma cells by inhibition of rna polymerase ii-dependent transcription and down-regulation of mcl-1. Cancer Res. 2005; 65:5399-5407.
• [27]Lolli G, Johnson LN. Recognition of cdk2 by cdk7. Proteins. 2007; 67:1048-1059.
• [28]Kaldis P, Solomon MJ. Analysis of cak activities from human cells. Eur J Biochem. 2000; 267:4213-4221.
• [29]Dirsch VM, Antlsperger DSM, Hentze H, Vollmar AM. Ajoene, an experimental anti-leukemic drug: mechanism of cell death. Leukemia. 2002; 16:74-83.
• [30]Wu J, Suzuki H, Zhou YW, Liu W, Yoshihara M, Kato M et al.. Cepharanthine activates caspases and induces apoptosis in jurkat and k562 human leukemia cell lines. J Cell Biochem. 2001; 82:200-214.
• [31]Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM. Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem. 1999; 274:5053-5060.
• [32]McCarthy NJ, Whyte MK, Gilbert CS, Evan GI. Inhibition of ced-3/ice-related proteases does not prevent cell death induced by oncogenes, dna damage, or the bcl-2 homologue bak. J Cell Biol. 1997; 136:215-227.
• [33]Green DR. Apoptotic pathways: the roads to ruin. Cell. 1998; 94:695-698.
• [34]Slee EA, Zhu H, Chow SC, MacFarlane M, Nicholson DW, Cohen GM. Benzyloxycarbonyl-val-ala-asp (ome) fluoromethylketone (z-vad.fmk) inhibits apoptosis by blocking the processing of cpp32. Biochem J. 1996; 315:21-24.
• [35]Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM et al.. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999; 397:441-446.
• [36]Garrofé-Ochoa X, Melero-Fernández de Mera RM, Fernández-Gómez FJ, Ribas J, Jordán J, Boix J. Bax and bak proteins are required for cyclin-dependent kinase inhibitory drugs to cause apoptosis. Mol Cancer Ther. 2008; 7:3800-3806.
• [37]Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F et al.. Elimination of mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 2003; 17:1475-1486.
• [38]Cosimo E, McCaig AM, Carter-Brzezinski LJM, Wheadon H, Leach MT, Le Ster K et al.. Inhibition of nf-κb-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes prosurvival stimuli to induce apoptosis in chronic lymphocytic leukemia cells. Clin Cancer Res. 2013; 19:2393-2405.
• [39]Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S et al.. Cdk inhibitors roscovitine and cr8 trigger mcl-1 down-regulation and apoptotic cell death in neuroblastoma cells. Genes Cancer. 2010; 1:369-380.
• [40]Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H et al.. Seliciclib (cyc202 or r-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of mcl-1 in multiple myeloma. Blood. 2005; 106:1042-1047.
• [41]Zheng Y, Shi Y, Tian C, Jiang C, Jin H, Chen J et al.. Essential role of the voltage-dependent anion channel (vdac) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene. 2004; 23:1239-1247.
• [42]Keinan N, Tyomkin D, Shoshan-Barmatz V. Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. Mol Cell Biol. 2010; 30:5698-5709.
• [43]Koss B, Morrison J, Perciavalle RM, Singh H, Rehg JE, Williams RT et al.. Requirement for antiapoptotic mcl-1 in the survival of bcr-abl b-lineage acute lymphoblastic leukemia. Blood. 2013; 122:1587-1598.
• [44]Holcik M, Korneluk RG. Xiap, the guardian angel. Nat Rev Mol Cell Biol. 2001; 2:550-556.
• [45]Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T et al.. Iap-family protein survivin inhibits caspase activity and apoptosis induced by fas (cd95), bax, caspases, and anticancer drugs. Cancer Res. 1998; 58:5315-5320.
• [46]Caldas H, Jiang Y, Holloway MP, Fangusaro J, Mahotka C, Conway EM et al.. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene. 2005; 24:1994-2007.
• [47]Obexer P, Ausserlechner MJ. X-linked inhibitor of apoptosis protein - a critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol. 2014; 4:197.
• [48]Badran A, Yoshida A, Wano Y, Imamura S, Kawai Y, Tsutani H et al.. Expression of the antiapoptotic gene survivin in chronic myeloid leukemia. Anticancer Res. 2003; 23:589-592.
• [49]Zhao J, Ma LM. Effect of bortezomib on reverse multidrug resistance and xiap expression in imatinib-resistant primary cells of chronic myeloid leukemia in blastic crisis. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013; 21:899-904.
• [50]Silva KL, Silva de Souza P, Nestal de Moraes G, Moellmann-Coelho A, da Cunha Vasconcelos F, Ciuvalschi Maia R. Xiap and p-glycoprotein co-expression is related to imatinib resistance in chronic myeloid leukemia cells. Leuk Res. 2013; 37:1350-1358.
• [51]van Loo G, Schotte P, van Gurp M, Demol H, Hoorelbeke B, Gevaert K et al.. Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent dna degradation. Cell Death Differ. 2001; 8:1136-1142.
• [52]Hedley DW, McCulloch EA. Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. Leukemia. 1996; 10:1143-1149.
• [53]Kim BM, Choi YJ, Lee YH, Joe YA, Hong SH. N, n-dimethyl phytosphingosine sensitizes hl-60/mx2, a multidrug-resistant variant of hl-60 cells, to doxorubicin-induced cytotoxicity through ros-mediated release of cytochrome c and AIF. Apoptosis. 2010; 15:982-993.
• [54]Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem. 2000; 275:7337-7342.
• [55]Jackson RC, Radivoyevitch T. Modelling c-abl signalling in activated neutrophils: the anti-inflammatory effect of seliciclib. Biodiscovery. 2013; 7:4.
• [56]Arsan ED, Coker A, Palavan-Ünsal N. Polyamine depletion enhances the roscovitine-induced apoptosis through the activation of mitochondria in hct116 colon carcinoma cells. Amino Acids. 2012; 42:655-665.