Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia
Tóm tắt
Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug–gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.
Từ khóa
Tài liệu tham khảo
Lowenberg, B. et al. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 364, 1027–1036 (2011).
Dohner, H. et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115, 453–474 (2010).
Dohner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).
de Rooij, J. D., Zwaan, C. M. & van den Heuvel-Eibrink, M. Pediatric AML: from biology to clinical management. J. Clin. Med. 4, 127–149 (2015).
Tallman, M. S., Gilliland, D. G. & Rowe, J. M. Drug therapy for acute myeloid leukemia. Blood 106, 1154–1163 (2005).
Hurle, M. R. et al. Computational drug repositioning: from data to therapeutics. Clin. Pharmacol. Ther. 93, 335–341 (2013).
Sukhai, M. A. et al. New sources of drugs for hematologic malignancies. Blood 117, 6747–6755 (2011).
Bartlett, J. B., Dredge, K. & Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314–322 (2004).
Essers, M. A. & Trumpp, A. Targeting leukemic stem cells by breaking their dormancy. Mol. Oncol. 4, 443–450 (2010).
Saito, Y. et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat. Biotechnol. 28, 275–280 (2010).
Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat. Biotechnol. 25, 1315–1321 (2007).
Costello, R. T. et al. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 60, 4403–4411 (2000).
Guzman, M. L. et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301–2307 (2001).
Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167–1174 (2006).
Guzman, M. L. et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105, 4163–4169 (2005).
Etxabe, A. et al. Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target. Leukemia 31, 2288–2302 (2017).
Sachlos, E. et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149, 1284–1297 (2012).
Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011).
Ng, S. W. et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature 540, 433–437 (2016).
Stegmaier, K. et al. Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation. Nat. Genet. 36, 257–263 (2004).
Hassane, D. C. et al. Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood 111, 5654–5662 (2008).
Lechman, E. R. et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 29, 214–228 (2016).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).
Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One 5, e13984 (2010).
Pabst, C. et al. Identification of small molecules that support human leukemia stem cell activity ex vivo. Nat. Methods 11, 436–442 (2014).
Lamb, J. The Connectivity Map: a new tool for biomedical research. Nat. Rev. Cancer 7, 54–60 (2007).
Mao, X. et al. Cyproheptadine displays preclinical activity in myeloma and leukemia. Blood 112, 760–769 (2008).
Garcia-Quiroz, J. et al. Astemizole synergizes calcitriol antiproliferative activity by inhibiting CYP24A1 and upregulating VDR: a novel approach for breast cancer therapy. PLoS One 7, e45063 (2012).
Jangi, S. M. et al. Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors. Carcinogenesis 29, 500–509 (2008).
Ellegaard, A. M. et al. Repurposing cationic amphiphilic antihistamines for cancer treatment. EBioMedicine 9, 130–139 (2016).
Wang, W. T. et al. Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation. Naunyn Schmiedebergs Arch. Pharmacol. 387, 33–45 (2014).
An, L. et al. Terfenadine combined with epirubicin impedes the chemo-resistant human non-small cell lung cancer both in vitro and in vivo through EMT and Notch reversal. Pharmacol. Res. 124, 105–115 (2017).
de Guadalupe Chavez-Lopez, M. et al. Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC. Tumour Biol. 36, 6149–6158 (2015).
Church, D. S. & Church, M. K. Pharmacology of antihistamines. World Allergy Organ. J. 4(3 Suppl), S22–S27 (2011).
Jakhar, R., Paul, S., Bhardwaj, M. & Kang, S. C. Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53-dependent crosstalk between autophagy and apoptosis. Cancer Lett. 372, 89–100 (2016).
Nicolau-Galmes, F. et al. Terfenadine induces apoptosis and autophagy in melanoma cells through ROS-dependent and -independent mechanisms. Apoptosis 16, 1253–1267 (2011).
Roderick, H. L. & Cook, S. J. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat. Rev. Cancer 8, 361–375 (2008).
Liu, J. D. et al. Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells. Mol. Carcinog. 37, 39–50 (2003).
Izumi-Nakaseko, H. et al. Possibility as an anti-cancer drug of astemizole: evaluation of arrhythmogenicity by the chronic atrioventricular block canine model. J. Pharmacol. Sci. 131, 150–153 (2016).
Calderon-Montano, J. M. et al. Evaluating the cancer therapeutic potential of cardiac glycosides. Biomed. Res. Int. 2014, 794930 (2014).
Raynal, N. J. et al. Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. Cancer Res. 76, 1494–1505 (2016).
Prassas, I. & Diamandis, E. P. Novel therapeutic applications of cardiac glycosides. Nat. Rev. Drug. Discov. 7, 926–935 (2008).
Segall, L., Javaid, Z. Z., Carl, S. L., Lane, L. K. & Blostein, R. Structural basis for alpha1 versus alpha2 isoform-distinct behavior of the Na,K-ATPase. J. Biol. Chem. 278, 9027–9034 (2003).
Barwe, S. P. et al. Novel role for Na,K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol. Biol. Cell 16, 1082–1094 (2005).
Wang, X. Q. et al. Apoptotic insults impair Na+, K+ -ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J. Cell Sci. 116(Pt 10), 2099–2110 (2003).
Xie, Z. & Cai, T. Na+ -K+–ATPase-mediated signal transduction: from protein interaction to cellular function. Mol. Interv. 3, 157–168 (2003).
Feng, Q., Leong, W. S., Liu, L. & Chan, W. I. Peruvoside, a cardiac glycoside, induces primitive myeloid leukemia cell death. Molecules 21, 534 (2016).
Tailler, M. et al. Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia. Oncogene 31, 3536–3546 (2012).
Hallbook, H. et al. Ex vivo activity of cardiac glycosides in acute leukaemia. PLoS One 6, e15718 (2011).
Haux, J., Klepp, O., Spigset, O. & Tretli, S. Digitoxin medication and cancer; case control and internal dose-response studies. BMC Cancer 1, 11 (2001).
Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).
Inaba, H. & Pui, C. H. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 11, 1096–1106 (2010).
Pui, C. H. et al. A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia 28, 2336–2343 (2014).
Ploner, C. et al. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22, 370–377 (2008).
Malani, D. et al. Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML. Leukemia 31, 1187–1195 (2017).
Simon, L. et al. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Clin. Cancer Res. 23, 6969–6981 (2017).
Miyoshi, H., Ohki, M., Nakagawa, T. & Honma, Y. Glucocorticoids induce apoptosis in acute myeloid leukemia cell lines with A t(8;21) chromosome translocation. Leuk. Res. 21, 45–50 (1997).
Ozbek, N., Erdemli, E., Hicsonmez, G., Okur, H. & Tekelioglu, M. Effects of methylprednisolone on human myeloid leukemic cells in vitro. Am. J. Hematol. 60, 255–259 (1999).
Rytting, M. et al. Intensively timed combination chemotherapy for the induction of adult patients with acute myeloid leukemia: long-term follow-up of a phase 2 study. Cancer 116, 5272–5278 (2010).
Lange, B. J. et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Blood 111, 1044–1053 (2008).