title: CD25 targeted therapy of chemotherapy resistant leukemic stem cells using DR5 specific TRAIL peptide.
abstract: Chemotherapy resistant leukemic stem cells (LSCs) are being targeted as a modern therapeutic approach to prevent disease relapse. LSCs isolated from methotrexate resistant side population (SP) of leukemic cell lines HL60 and MOLT4 exhibited high levels of CD25 and TRAIL R2/DR5 which are potential targets. Recombinant immunotoxin conjugating IL2α with TRAIL peptide mimetic was constructed for DR5 receptor specific targeting of LSCs and were tested in total cell population and LSCs. IL2-TRAIL peptide induced apoptosis in drug resistant SP cells from cell lines and showed potent cytotoxicity in PBMCs derived from leukemic patients with an efficacy of 81.25% in AML and 100% in CML, ALL and CLL. IL2-TRAIL peptide showed cytotoxicity in relapsed patient samples and was more effective than TRAIL or IL2-TRAIL proteins. Additionally, DR5 specific IL2-TRAIL peptide was effective in targeting and killing LSCs purified from cell lines [IC50: 952nM in HL60, 714nM in MOLT4] and relapsed patient blood samples with higher efficacy (85%) than IL2-TRAIL protein (46%). Hence, CD25 and DR5 specific targeting by IL2-TRAIL peptide may be an effective strategy for targeting drug resistant leukemic cells and LSCs.
authors.affiliation: Bhupat & Jyoti Mehta School of Biosciences Building, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
authors.forename: Jayaprakasam
authors.initials: J
authors.lastname: Madhumathi
authors.affiliation: Bhupat & Jyoti Mehta School of Biosciences Building, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
authors.forename: Surapally
authors.initials: S
authors.lastname: Sridevi
authors.affiliation: Bhupat & Jyoti Mehta School of Biosciences Building, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India. Electronic address: vermars@iitm.ac.in.
authors.forename: Rama Shanker
authors.initials: RS
authors.lastname: Verma
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008727:Methotrexate / Q000627:therapeutic use / Q000633:toxicity; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry*
chemical_list: D000922:Immunotoxins; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D008727:Methotrexate
keywords: DR5 receptor; Drug resistance; Immunotoxin; Leukemic stem cells; TRAIL