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

Abstract

Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required. Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels. In the present study, we demonstrated that PL induced cancer cell death through, at least in part, the induction of ferroptosis, as the cancer cell-killing activity was inhibited by the antioxidant, N‑acetylcysteine, ferroptosis inhibitors (ferrostatin‑1 and liproxstatin‑1) and the iron chelator, deferoxamine (DFO), but not by the apoptosis inhibitor, Z-VAD-FMK, or the necrosis inhibitor, necrostatin‑1. Cotylenin A (CN‑A; a plant growth regulator) exhibits potent antitumor activities in several cancer cell lines, including pancreatic cancer cell lines. We found that CN‑A and PL synergistically induced the death of pancreatic cancer MIAPaCa‑2 and PANC‑1 cells for 16 h. CN‑A enhanced the induction of ROS by PL for 4 h. The synergistic induction of cell death was also abrogated by the ferroptosis inhibitors and DFO. The present results revealed that clinically approved sulfasalazine (SSZ), a ferroptosis inducer, enhanced the death of pancreatic cancer cells induced by PL and the combined effects were abrogated by the ferroptosis inhibitors and DFO. SSZ further enhanced the cancer cell-killing activities induced by combined treatment with PL plus CN‑A. On the other hand, the synergistic induction of cell death by PL and CN‑A was not observed in mouse embryonic fibroblasts (MEFs), and SSZ did not enhance the death of MEFs induced by PL plus CN‑A. These results suggest that the triple combined treatment with PL, CN‑A and SSZ is highly effective against pancreatic cancer.

Ferroptosis: past, present and future

“…In addition, the combination of Cotylenin A (CN-A) and phenylethyl isothiocyanate (PEITC) induces the production of ROS and triggers ferroptosis, thus inhibiting the proliferation of various pancreatic cancer cells (such as MIAPaCa-2 and PANC-1 cell lines). Recent studies have found that a more effective combination of Piperlongumine (PL), CN-A and sulfasalazine (a ferroptosis inducer) significantly promotes ferroptosis in the pancreatic cancer cell lines MIAPaCa-2 and PANC-1 35 .…”

Matching cell lines with cancer type and subtype of origin via mutational, epigenomic and transcriptomic patterns

“…Similarly, for pancreatic adenocarcinoma, benefits were observed by focusing on cell lines that resemble the corresponding cancer type better: using only the ‘golden set’ plus ‘silver set’ cell lines, 10 new significant associations were found (Fig 4b). For instance, we detected that SMAD4-mutant cell lines are more resistant to piperlongumine, a natural product claimed to have antitumor properties exerted via multiple pathways (42,43). Mutations of the tumor suppressor gene EP300 were associated with higher sensitivity to three drugs in pancreatic cancer cell lines (Fig 4d).…”

The role of ferroptosis in digestive system cancer (Review)

“…Piperlongumine (PL) induces human pancreatic cancer cell line death by substantially increasing the intracellular ROS level. This effect was inhibited by ferroptosis inhibitors and iron chelators but not apoptosis or necrosis inhibitors, suggesting that PL induced cell death by ferroptosis (15). Furthermore, the aforementioned study revealed that triple combined therapy with PL, CN-A and sulfasalazine had a high efficacy in pancreatic cancer in vitro (15).…”

“…Ferroptosis was revealed to be involved in various types of digestive system cancer, excluding esophageal and biliary system cancer (9,(12)(13)(14)(15). The mechanisms of ferroptosis in digestive system cancer are presented in Table I and Fig.…”

“…Pancreatic cancer is one of the most lethal types of digestive malignancies, and current chemotherapeutic drugs are often ineffective. Previous studies suggested that certain natural plant extracts possess a potential therapeutic effect in pancreatic cancer cells by inducing ferroptosis (15,18,26,27). The combination of cotylenin A (CN-A) and phenethyl isothiocyanate synergistically induced pancreatic cancer cell death by the generation of ROS, which drives ferroptosis (26).…”