Small-molecule MDM2 inhibitor LQFM030-induced apoptosis in p53-null K562 chronic myeloid leukemia cells.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ genetics
BALB 3T3 Cells
Enzyme Inhibitors
/ pharmacology
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ drug therapy
Mice
Mutation
Piperidines
/ pharmacology
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Pyrazoles
/ pharmacology
Signal Transduction
Tumor Suppressor Protein p53
/ deficiency
MDM2
chronic myeloid leukemia
drug discovery
nutlins
p53
Journal
Fundamental & clinical pharmacology
ISSN: 1472-8206
Titre abrégé: Fundam Clin Pharmacol
Pays: England
ID NLM: 8710411
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
25
09
2019
revised:
28
01
2020
accepted:
30
01
2020
pubmed:
6
2
2020
medline:
21
4
2021
entrez:
4
2
2020
Statut:
ppublish
Résumé
Our group designed and synthesized the N-phenyl-piperazine LQFM030 [1-(4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl) piperazin-1-yl) ethanone], a small molecule derived from molecular simplification of the Nutlin-1, an inhibitor of the human homologue of murine double minute 2 (MDM2) protein that is expressed in several types of cancer. To better investigate the effects of LQFM030 regarding the p53 mutation status, this study investigated the antiproliferative activity of LQFM030 against the p53-null K562 leukemia cells as well as the cell death pathways involved. In addition, the effects of LQFM030 on the levels of the p53/MDM2 complex were also carried out using 3T3 cells as a p53 wild-type model. Our data suggest that LQFM030 triggered apoptosis in K562 cells via different mechanisms including cell cycle arrest, caspase activation, reduction of mitochondrial activity, decrease in MDM2 expression, and transcriptional modulation of MDMX, p73, MYC, and NF-ĸB. Additionally, it promoted effects in p53/MDM2 binding in p53 wild-type 3T3 cells. Therefore, LQFM030 has antiproliferative effects in cancer cells by a p53 mutation status-independent manner with different signaling pathways. These findings open new perspectives to the treatment of leukemic cells considering the resistance development associated with cancer treatment with conventional cytotoxic drugs.
Substances chimiques
Antineoplastic Agents
0
Apoptosis Regulatory Proteins
0
Enzyme Inhibitors
0
LQFM030
0
Piperidines
0
Pyrazoles
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
444-457Subventions
Organisme : Fundação de Amparo à Pesquisa do Estado de Goiás
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : Finance code 001
Organisme : Financiadora de Estudos e Projetos
Informations de copyright
© 2020 Société Française de Pharmacologie et de Thérapeutique.
Références
Deininger M.W., Goldman J.M., Melo J.V. The molecular biology of chronic myeloid leukemia. Blood (2000) 96 3343-3356.
Chen Y., Peng C., Li D., Li S. Molecular and cellular bases of chronic myeloid leukemia. Protein cell (2010) 1 124-32.
Marum J.E., Branford S. Current developments in molecular monitoring in chronic myeloid leukemia. Ther. Adv. Hematol. (2016) 7 237-251.
Saikia T. The cure of chronic myeloid leukemia: are we there yet? Curr. Oncol. Rep. (2018) 20 12.
Bauer S., Buchanan S., Ryan I. Tyrosine kinase inhibitors for the treatment of chronic-phase chronic myeloid leukemia: long-term patient care and management. J. Adv. Pract Oncol. (2016) 7 42-54.
Zhao Y., Aguilar A., Bernard D., Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J. Med. Chem. (2015) 58 1038-1052.
Tisato V., Voltan R., Gonelli A., Secchiero P., Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J. Hematol Oncol. (2017) 10 133.
Nero T.L., Morton C.J., Holien J.K., Wielens J., Parker M.W. Oncogenic protein interfaces: small molecules, big challenges. Nat. Rev. Cancer. (2014) 14 248.
Feki A., Irminger-Finger I. Mutational spectrum of p53 mutations in primary breast and ovarian tumors. Cri. Rev. Oncol. Hematol. (2004) 52 103-116.
Karni-Schmidt O., Lokshin M., Prives C. The roles of MDM2 and MDMX in cancer. Annu. Rev. Pathol. (2016) 11 617-644.
Cheok C.F., Lane D.P. Exploiting the p53 pathway for therapy. Cold Spring Harb. Perspect Med. (2017) 7 a026310.
Simabuco F.M., Morale M.G., Pavan I.C.B., Morelli A.P., Silva F.R., Tamura R.E. p53 and metabolism: from mechanism to therapeutics. Oncotarget. (2018) 9 23780-23823.
Wu X., Bayle J.H., Olson D., Levine A.J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. (1993) 7 1126-1132.
Oliner J.D., Kinzler K.W., Meltzer P.S., George D.L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature (1992) 358 80-83.
Daujat S., Neel H., Piette J. MDM2: life without p53. Trends Genet. (2001) 17 459-464.
Thomasova D., Mulay S.R., Bruns H., Anders H.-J. p53-independent roles of MDM2 in NF-κB signaling: implications for cancer therapy, wound healing, and autoimmune diseases. Neoplasia (2012) 14 1097-1101.
Walsh E.M., Niu M., Bergholz J., Xiao Z.-X.J. Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation. Biochem. Biophys. Res. Comm. (2015) 461 293-299.
Vassilev L.T., Vu B.T., Graves B., et al. In Vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (2004) 303 844-848.
Lau L.M.S., Nugent J.K., Zhao X., Irwin M.S. HDM2 antagonist nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene (2008) 27 997-1003.
Secchiero P., Bosco R., Celeghini C., Zauli G. Recent advances in the therapeutic perspectives of nutlin-3. Curr. Pharm. Des. (2011) 17 569-577.
Shangary S., Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol. (2009) 49 223-241.
da Mota M.F., Cortez A.P., Benfica P.L., et al. Induction of apoptosis in ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor - LQFM030. J. Pharm. Pharmacol. (2016) 68 1143-1159.
da Mota M.F., de Carvalho F.S., de Ávila R.I., et al. LQFM030 reduced ehrlich ascites tumor cell proliferation and VEGF levels. Life Sci. (2018) 201 1-8.
Costa F.B., Cortez A.P., de Ávila R.I., et al. The novel piperazine-containing compound LQFM018: necroptosis cell death mechanisms, dopamine D4 receptor binding and toxicological assessment. Biomed. Pharmacother. (2018) 102 481-493.
Arva N.C., Talbott K.E., Okoro D.R., Brekman A., Qiu W.G., Bargonetti J. Disruption of the p53-Mdm2 complex by nutlin-3 reveals different cancer cell phenotypes. Ethn. Dis. (2008) 18 S2-S8.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods (1983) 65 55-63.
Rosenfeld G. Pancromic staining for clinical hematology and cytology: a novel combination of may-grunwald and giemsa components in one rapid usage staining. Mem. Inst. Butantan. (1947) 20 329-335.
Cheng K.-C., Huang H.-C., Chen J.-H., et al. Ganoderma lucidum polysaccharides in human monocytic leukemia cells: from gene expression to network construction. BMC Genom. (2007) 8 411.
Yu F.-S., Huang A.-C., Yang J.-S., et al.Safrole induces cell death in human tongue squamous cancer SCC-4 cells through mitochondria-dependent caspase activation cascade apoptotic signaling pathways. Environ. Toxicol. (2012) 27 433-444.
Li B., Cheng Q., Li Z., Chen J. p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors. Cell cycle (2010) 9 1411-1420.
Lee U.J., Choung S.-R., Prakash K.V.B., et al. Dual knockdown of p65 and p50 subunits of NF-kappaB by siRNA inhibits the induction of inflammatory cytokines and significantly enhance apoptosis in human primary synoviocytes treated with tumor necrosis factor-alpha. Mol. Biol. Rep. (2008) 35 291-298.
Concin N., Becker K., Slade N., et al. Transdominant ΔTAp73 Isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors <strong><em>in Vivo</em></strong>. Can. Res. (2004) 64 2449-2460.
Pandey V., Qian P.-X., Kang J., et al. Artemin stimulates oncogenicity and invasiveness of human endometrial carcinoma cells. Endocrinology (2010) 151 909-920.
Vandesompele J., De Preter K., Pattyn F., et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. (2002) 3 1-12.
Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods (2001) 25 402-408.
Hasegawa H., Yamada Y., Iha H., et al. Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. Leukemia (2009) 23 2090-2101.
Drakos E., Singh R.R., Rassidakis G.Z., et al. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). Leukemia (2011) 25 856-867.
Trino S., Iacobucci I., Erriquez D., et al. Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients. Oncotarget (2016) 7 12951-12961.
Abbastabar M., Kheyrollah M., Azizian K., et al. Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: a double-edged sword protein. DNA Repair (2018) 69 63-72.
Saha M.N., Jiang H., Chang H. Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways. Cancer Biol. Ther. (2010) 10 567-578.
Vogel C., Marcotte E.M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. (2012) 13 227-232.
Dias T.R., Rato L., Martins A.D., et al. Insulin deprivation decreases caspase-dependent apoptotic signaling in cultured rat sertoli cells. ISRN Urology (2013) 2013 8.
Galluzzi L., Vitale I., Aaronson S.A., et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. (2018) 25 486-541.
Landry Y., Gies J. Drugs and their molecular targets: an updated overview. Fundam. Clin. Pharmacol. (2008) 22 1-18.
Feeley K.P., Adams C.M., Mitra R., Eischen C.M. Mdm2 is required for survival and growth of p53-deficient cancer cells. Can. Res. (2017) 77 3823-3833.
Beck Z., Kiss A., Tóth F.D., et al. Alterations of P53 and RB genes and the evolution of the accelerated phase of chronic myeloid leukemia. Leuk. Lymphoma. (2000) 38 587-597.
Du W., Wu J., Walsh E.M., Zhang Y., Chen C.Y., Xiao Z.-X.J. Nutlin-3 affects expression and function of retinoblastoma protein: role of retinoblastoma protein in cellular response to nutlin-3. J. Biol. Chem. (2009) 284 26315-26321.
Hu B., Gilkes D.M., Farooqi B., Sebti S.M., Chen J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin. J. Biol. Chem. (2006) 281 33030-33035.
Woo S.-M., Choi Y.K., Kim A.J., Cho S.-G., Ko S.-G. p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells. Mol Med Rep. (2016) 13 1091-1096.
dos Santos T.R.M., Garcia da Silva A.C., de Carvalho F.S., et al. Toxico-pharmacological evaluations of the small-molecule LQFM166: Inducer of apoptosis and MDM2 antagonist. Chem. Biol. Interact. (2018) 293 20-27.
Xia Y., Shen S., Verma I.M. NF-κB, an active player in human cancers. Cancer Immunol. Res. (2014) 2 823-830.
Mobaraki R.N., Karimi M., Alikarami F., et al. RITA induces apoptosis in p53-null K562 leukemia cells by inhibiting STAT5, Akt, and NF-κB signaling pathways. Anticancer Drugs (2018) 29 847-853.
Bretones G., Delgado M.D., León J. Myc and cell cycle control. Biochim. Biophys. Acta. (2015) 506-516.
Albajar M., Gómez-Casares M.T., Llorca J., et al. MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib. Mol. Cancer Res. (2011) 9 564-576.
Peterson L.F., Mitrikeska E., Giannola D., et al. p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. Leukemia (2011) 25 761.
Pflaum J., Schlosser S., Müller M. p53 family and cellular stress responses in cancer. Front. Oncol. (2014) 4 285.
Murray-Zmijewski F., Lane D.P., Bourdon J.C. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. (2006) 13 962.
Tschan M.P., Grob T.J., Peters U.R., et al. Enhanced p73 expression during differentiation and complex p73 isoforms in myeloid leukemia. Biochem. Biophys. Res. Comm. (2000) 277 62-65.
Perret G.Y., Crépin M. New pharmacological strategies against metastatic spread. Fundam. Clin. Pharmacol. (2008) 22 465-492.