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.

Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells

“…Furthermore, the immunoproteasome is slightly more efficient than the 20S proteasome in recognizing and degrading nascent oxidant-damaged proteins [33]. Recent studies have demonstrated that piperlongumine contributes to cancer cell death by targeting stress responses to ROS [9, 34–36]. Consistent with these studies, we found that piperlongumine increased intracellular ROS levels in MM cells.…”

“…Piperlongumine is an alkaloid isolated from the long pepper ( Piper longum L. ) that possesses anti-inflammatory, anti-platelet aggregation, and anti-tumor properties [7–9]. Piperlongumine exerts anti-tumor effects through a variety of pathways, including the induction of reactive oxygen species (ROS) accumulation, activation of C/EBP homologous protein (CHOP), suppression of LMP-1 (EBV-encoded oncogene) expression, activation of AMPK phosphorylation, inhibition of NF-κB, and promotion of autophagy [10–17].…”

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

“…Notably, the GC resistance‐promoting role of MYC in ALL was firstly elucidated by Renner K . Han et al revealed that MYC displays constitutive activation in B‐ALL cell lines, especially GC‐resistant B‐ALL, indicating the critical role of MYC in evolution of GC resistance . The positive impact of MYC on progression of GC resistance in ALL was subsequently strengthened by other studies .…”

“…Despite the reassuring achievements in the treatment of patients with ALL, resistance to GC agonists has been a major obstacle in eliminating leukemia cells and maximizing cure . Several studies on GC resistance have elucidated that GC‐stimulated apoptosis is not induced in leukemia cells with poor response to GC agents . Recently published articles partly expanded our understanding about the molecular mechanism of GC resistance, wherein the role of some molecules and signaling pathways including MLL rearrangement and JAK/SAT pathway alteration were determined.…”

Integrated analysis of microRNA and transcription factor reveals important regulators and regulatory motifs in adult B-cell acute lymphoblastic leukemia

“…As a member of the helix-loop-helix/ leucine-zipper transcription factor family, MYC is a master regulator of important biological processes such as cell survival, proliferation, differentiation, metabolism and pluripotency maintenance (58,59). Constitutive activation of MYC exhibited in a variety of B-ALL cell lines (60). Double transgenesis of MYC and Bcl-2 caused hyperproliferation of pre-B and B cells and promoted initiation of B-ALL in mice (51).…”