Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Abstract

Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-kB, and suppressed the NF-kB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-kB-and NF-kB-regulated gene products.Cancer Prev Res; 9(3); 234-44. Ó2015 AACR.

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

“…PL has been tested for its synergistic anti-tumor effect in combination with TNF-related apoptosis-inducing ligand [46], ataxia telangiectasia and Rad3-related protein inhibition [50], or a chemotherapeutic agent, such as cisplatin [33, 34], paclitaxel [34], docetaxel [51], and gemcitabine [39]. Thus, we investigated the synergistic senolytic effect of PL and ABT-263 on IR-SCs.…”

Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis

“…Zou et al recently reported that PL interacted with thioredoxin reductase 1 to induce the ROS-mediated apoptosis of human gastric cancer cells (35). In addition, PL has been shown to promote cell death by activating several mechanisms, including apoptosis, autophagy and necrosis, affecting the PI3K/AKT/mTOR, p38/JNK, MEK/ERK and NF-κB pathways (22,(27)(28)(29)36). In the present study, we found that PL alone induced the death of pancreatic cancer cells, at least in part, by the induction of ferroptosis, the execution of which requires the accumulation of ROS in an iron-dependent manner (16).…”

Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents

“…Compound 1 and seven analogues (7)(8)(9)(10)(11)(12)(13) were obtained in moderate yields via a one-pot reaction between 6 and appropriately substituted cinnamic acids, pre-activated with pivaloyl chloride (Scheme 1, steps iii and iv, 61-72% yield) [15]. 1 H NMR coupling constants (15)(16) Hz) indicated a trans configuration around the linear α,β-unsaturated double bond.…”

“…Compound 1 has been recently reported to be a direct STAT3 inhibitor [4], a proteasome inhibitor [5], to promote autophagy [6], and to modulate NF-κB and NF-κB-regulated gene products [7].…”