Piperlongumine induces G2/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway

Thongsom, Sunisa; Suginta, Wipa; Lee, Kyung Jin; Choe, Han; Talabnin, Chutima

doi:10.1007/s10495-017-1422-y

Cited by 69 publications

(67 citation statements)

References 36 publications

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“…Piplartine also reversed doxorubicin resistance in K562/A02 human leukemia cells by PI3K/Akt pathway [21] . Moreover, piplartine also induced apoptosis through activation of ERK signaling in cholangiocarcinoma and colon carcinoma cell lines [51] , [52] .…”

Section: Discussionmentioning

confidence: 94%

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

et al. 2019

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Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.

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Section: Discussionmentioning

confidence: 94%

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

et al. 2019

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“… 74 On the other hand, molecular mechanism of PL may be related with influence on GSTP1, ROS-JNK-ERK, or the phosphorylation of JAK1,2/STAT3 signaling pathway. 15 , 74 , 75 …”

Section: Discussionmentioning

confidence: 99%

The effect of piperlongumine on endothelial and lung adenocarcinoma cells with regulated expression of profilin-1

Gagat

Hałas‐Wiśniewska

Zielińska

et al. 2018

OTT

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PurposeThe aim of the study was to evaluate the effect of piperlongumine (2 and 4 µM) on endothelial EA.hy926 and lung adenocarcinoma A549 cells with regulated expression of profilin-1 (PFN1).Material and methodsThe cytotoxicity of alkaloid was evaluated by MTT assay, while cell death was assessed using double staining with annexin V and propidium iodide. Subsequently, the level of PFN1 1) upregulation in EA.hy926 endothelial cells and 2) downregulation in A549 lung adenocarcinoma cells. The next step was the analysis of the effect of PFN1 manipulation on cytoskeletal proteins.ResultsThe results showed that piperlongumine may inhibit proliferation of EA.hy926 and A549 cell lines and also induce cell death in a dose-dependent manner. Furthermore, endothelial cells with PFN1 overexpression showed lower sensitivity to alkaloid and strengthening of cell–cell interactions. In the case of A549 cells, loss of PFN1 expression resulted in a lower percentage of early apoptotic cells, reorganization of F-actin and vimentin network, and reduction of migratory potential.ConclusionWe suggest that upregulation of PFN1 in endothelial cell line may stabilize the cell junctions. In turn, PFN1 downregulation in A549 cells probably suppresses cell migration and sensitizes cells to anticancer agents.

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“…Although it has been proven that autophagy induction is necessary for their mechanism of action, the specific molecular mechanisms governing their autophagy modulation abilities are not fully understood yet. Piperlongumine induced apoptosis [155] and autophagy [151] in CCA cells through the production of ROS, induction of ER stress and activation of JNK-ERK signaling pathway [151]. Similar to piperlongumine, dihydroartemisinin is an antimalaria drug that induces ROS-mediated ER stress through DAPK activation, promoting the disruption of Beclin1-Bcl-2 complex and inducing autophagy-mediated CCA cell death, therefore activating initiation of autophagy.…”

Section: Autophagy Activatorsmentioning

confidence: 99%

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.

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Piperlongumine induces G2/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway

Cited by 69 publications

References 36 publications

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

The effect of piperlongumine on endothelial and lung adenocarcinoma cells with regulated expression of profilin-1

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

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