G-quadruplex forming region within WT1 promoter is selectively targeted by daunorubicin and mitoxantrone: A possible mechanism for anti-leukemic effect of drugs
Wilms tumor 1 (WT1) has long been overexpressed in acute myeloid leukemia and has a prognostic value in its diagnosis. Lately, the formation of G-quadruplexes in oncogenic promoters like WT1 has been widely investigated since stabilization of these structures leads to transcriptional inhibition of the oncogene. Daunorubicin and mitoxantrone considered as crucial components of almost all standard acute myeloid leukemia induction regimens. Herein we have proposed a probable molecular mechanism of action through which the drugs may stabilize WT1 promoter G-quadruplexes. Differential pulse voltammetry, circular dichroism, and polyacrylamide gel electrophoresis, electrophoretic mobility shifts assay, polymerase chain reaction (PCR) stop assays, and quantitative RT-PCR were performed in order to better understanding the nature of interactions between the drugs and G-quadruplexes. Data revealed that both drugs had potential to stabilize G-quadruplexes and down-regulate WT1 transcription but daunorubicin exposed more silencing impact. The results illustrated the therapeutic association of these two commercial FDA-approved drugs in WT1 transcriptional down-regulation. Since WT1 has known as a transcriptional regulator of at least 137 target genes, so the new data are significant for the development of new approaches to regulating WT1 and other target genes by employing special drugs in cancer treatment.
KeywordsDaunorubicin mitoxantrone promoter G-quadruplexes WT1 down-regulation
We would like to acknowledge the helpful comments of Prof. Jahan-bakhsh Raoof on this study.
- Bassam BJ and Gresshoff PM 2007 Silver staining DNA in polyacrylamide gels. Nat. Protoc. 2 2649–2654Google Scholar
- Casagrande V, Salvati E, Alvino A, Bianco A, Ciammaichella A, D’Angelo C, Ginnari-Satriani L, Serrilli AM, Iachettini S, Leonetti C and Neidle S 2011 N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage. J. Med. Chem. 54 1140-56CrossRefGoogle Scholar
- Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F, Rege-Cambrin G, Guerrasio A, Divona M, Coco FL and Saglio G 2002 Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 16 2115–2121CrossRefGoogle Scholar
- Cilloni D, Renneville A, Hermitte F Hills RK, Daly S, Jovanovic JV, Gottardi E, Fava M, Schnittger S, Weiss T and Izzo B 2009 Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: A European Leukemia Net study. J. Clin. Oncol. 27 5195–5201Google Scholar
- Cogoi S and Xodo LE 2006 G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res. 34 2536–2549Google Scholar
- Garg M, Moore H, Tobal Kand Liu Yin JA 2003 Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia. Br. J. Haematol. 123 49–59Google Scholar
- Ghazaey Zidanloo S and Hosseinzadeh Colagar A 2014 Geographic heterogeneity of the AML1-ETO fusion gene in Iranian patients with acute myeloid leukemia. RBMB 3 1–7Google Scholar
- Ghazaey Zidanloo S and Jafarzadeh Hesari M 2018 In silico screening of G-quadruplex structures in Wilms tumor 1 gene promoter. J. North Khorasan Univ. Med. Sci. Google Scholar
- Ghazaey Zidanloo S, Hosseinzadeh CA, Ayatollahi H, Raoof JB 2016 Down-regulation of the WT1 gene expression via TMPyP4 stabilization of promoter G-quadruplexes in leukemia cells. Tumor Biol. 37 1–11Google Scholar
- Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A, Kim EH, Hosen N, Murakami M, Fujioka T and Masuda T 2003 The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 101 1698–1704CrossRefGoogle Scholar
- Tatsumi N, Oji Y, Tsuji N, Tsuda A, Higashio M, Aoyagi S, Fukuda I, Ito K, Nakamura J, Takashima S and Kitamura Y 2008 Wilms’tumor gene WT1-shRNA as a potent apoptosis inducing agent for solid tumors. Int. J. Oncol. 32 701–711Google Scholar
- Zhang R, Lin Yand Zhang CT 2008 Greglist: a database listing potential G-quadruplex regulated genes. Nucleic Acids Res. 36 D372–D376Google Scholar