title: Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance.
abstract: Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL.
authors.affiliation: Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. Electronic address: seong-su-han@uiowa.edu.
authors.forename: Seong-Su
authors.initials: SS
authors.lastname: Han
authors.affiliation: Health and Human Physiology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Han
authors.affiliation: Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Kamberos
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004148:Dioxolanes / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D031701:Piper / Q000737:chemistry*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D010881:Piperidones
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D064107:Aurora Kinase B; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D004148:Dioxolanes; D050687:E2F1 Transcription Factor; D005938:Glucocorticoids; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D020598:Proto-Oncogene Proteins c-myb; D000071701:Regulatory Factor X Transcription Factors; D055751:SOXC Transcription Factors; D000077022:Survivin; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins; C107489:BIRC5 protein, human; C493753:E2F1 protein, human; C083431:SOX4 protein, human; C576921:AURKB protein, human; C498077:piperlongumine; D010881:Piperidones
keywords: B-acute lymphoblastic leukemia; GC-resistance; Piperlongumine; Transcription factors