Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways

Wang, Hongfei; Wang, Yongqiang; Gao, Hongmei; Wang, Bing; Dou, Lin; Yin, Li

doi:10.3892/ol.2017.7498

Cited by 15 publications

(17 citation statements)

References 37 publications

(47 reference statements)

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“…Co-treatment with p38 MAPK inhibitor reduced the complexes-induced apoptosis in HCT116 cells, and was also confirmed by quantification of the levels of phosphorylation of p38α (T180/Y182), indicating p38 MAPK-mediated apoptosis. Wang et al (37) reported that piplartine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways. Moreover, a platinum complex with piplartine caused ROS-mediated apoptosis by ERK1/2/p38 pathway in human acute promyelocytic leukemia HL-60 cells (17).…”

Section: Discussionmentioning

confidence: 99%

Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model

et al. 2019

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Ruthenium complexes with piplartine, [Ru(piplartine)(dppf)(bipy)](PF 6 ) 2 ( 1 ) and [Ru(piplartine)(dppb)(bipy)](PF 6 ) 2 ( 2 ) (dppf = 1,1-bis(diphenylphosphino) ferrocene; dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2′-bipyridine), were recently synthesized and displayed more potent cytotoxicity than piplartine in different cancer cells, regulated RNA transcripts of several apoptosis-related genes, and induced reactive oxygen species (ROS)-mediated apoptosis in human colon carcinoma HCT116 cells. The present work aimed to explore the underlying mechanisms through which these ruthenium complexes induce cell death in HCT116 cells in vitro , as well as their in vivo action in a xenograft model. Both complexes significantly increased the percentage of apoptotic HCT116 cells, and co-treatment with inhibitors of JNK/SAPK, p38 MAPK, and MEK, which inhibits the activation of ERK1/2, significantly reduced the apoptosis rate induced by these complexes. Moreover, significant increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182), and phospho-ERK1 (T202/Y204) expressions were observed in cells treated with these complexes, indicating MAPK-mediated apoptosis. In addition, co-treatment with a p53 inhibitor (cyclic pifithrin-α) and the ruthenium complexes significantly reduced the apoptosis rate in HCT116 cells, and increased phospho-p53 (S15) and phospho-histone H2AX (S139) expressions, indicating induction of DNA damage and p53-dependent apoptosis. Both complexes also reduced HCT116 cell growth in a xenograft model. Tumor mass inhibition rates were 35.06, 29.71, and 32.03% for the complex 1 (15 μmol/kg/day), complex 2 (15 μmol/kg/day), and piplartine (60 μmol/kg/day), respectively. These data indicate these ruthenium complexes as new anti-colon cancer drugs candidates.

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Section: Discussionmentioning

confidence: 99%

Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model

et al. 2019

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“…Drugs that induce ROS production may promote cancer cell death by activating autophagy. PL has been reported to induce autophagy in kidney, prostate and breast cancer (23), and leukemia cells (38). The increase in LC3-II was reversed by the application of NAC prior to PL treatment, suggesting that ROS were involved in autophagy induction.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous signaling pathways can be involved in autophagy induction. Previously, it was reported that PL exhibits anticancer activity by affecting PI3K/AKT, p38/JNK, MEK/Erk and NF-κB signaling pathways in cancer cells (24,38-40). In the present study, only the Erk pathway was analyzed; it was revealed that the Erk pathway was involved in the anticancer activity of PL in HuCCT-1 cells.…”

Section: Discussionmentioning

confidence: 99%

Piperlongumine induces autophagy in biliary cancer cells via�reactive oxygen species-activated Erk signaling pathway

et al. 2019

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Biliary cancer (BC) is an aggressive neoplasm with high mortality. BC can be categorized into three groups: Intrahepatic cholangiocarcinoma (CCA; also known as bile duct cancer), extrahepatic cholangiocarcinoma and gallbladder cancer. Due to its heterogeneity and aggressiveness, the response to current chemotherapy and radiotherapy methods in patients with BC is poor. Therefore, there is an urgent requirement to develop drugs to treat BC. Piperlongumine (PL), a naturally occurring small molecule isolated from Piper longum L., exhibits anticancer activity by inducing reactive oxygen species (ROS) production. In the present study, the effects of PL on cell proliferation, cell cycle, apoptosis and autophagy in BC cells were investigated. PL induced BC cell death in a concentration- and time-dependent manner by inducing ROS production. PL induced cell cycle arrest in CCA cells (HuCCT-1) and gallbladder cancer cells (OCUG-1) cells, but with distinct cell cycle distribution profiles. PL caused G2/M cell cycle arrest in HuCCT-1 cells, and G0/G1 cell cycle arrest in OCUG-1 cells. PL induced apoptosis and autophagy; PL treatment induced accumulation of LC3-II in a concentration- and time-dependent manner. The Erk signaling pathway appeared to be involved in autophagy induction. Application of the ROS scavenger, N-acetyl-l-cysteine, to BC cells attenuated the cell death, cell cycle arrest, apoptosis and autophagy induced by PL treatment. These findings indicated that PL may be a potential agent for BC treatment in the future.

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“…p38 MAPK activation through phosphorylation (P-p38) is involved in cell differentiation, autophagy, and apoptosis. [37][38][39] NF-kB p65 subunit/RELA is a protein that in humans is encoded by the RELA gene. RELA as part of NF-kB heterodimer complex is retained in cytosol; upon activation, RELA is translocated into the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Ferruginol induced apoptosis on SK-Mel-28 human malignant melanoma cells mediated through P-p38 and NF-κB

Jia

Zhang

et al. 2018

Hum Exp Toxicol

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In the present investigation, the antitumor effect of ferruginol (FGL) in SK-Mel-28 human malignant melanoma cells was studied. To investigate the cytotoxic property of FGL, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used. Results revealed that prolonged treatment duration decreases the IC25, IC50, and IC75 concentrations of FGL. The cytotoxicity was further confirmed by lactate dehydrogenase assay. As evident from comet assay, FGL induces DNA damage in a dose-dependent manner. Annexin V and 7-ADD assays showed that FGL-induced DNA damage triggers apoptosis-mediated cell death as confirmed by caspase-3 activity assay. As seen through Western blotting, FGL increases phosphorylation of p38 and nuclear translocation of NF-κB. Further, it was observed that p38 phosphorylation is responsible for NF-κB translocation to the nucleus. Further, inhibition of p38 phosphorylation and translocation of NF-κB decrease caspase-3 activity. The above finding confirms that caspase-3 activation is mediated through P-p38 and nuclear translocation of NF-κB. The present findings indicate that FGL significantly suppresses the proliferation of SK-Mel-28 cells in a dose- and time-dependent manner through induction of apoptosis. Furthermore, FGL executes apoptosis through phosphorylation of key protein such as p38 and translocation of NF-κB into the nucleus.

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Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways

Cited by 15 publications

References 37 publications

Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model

Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model

Piperlongumine induces autophagy in biliary cancer cells via�reactive oxygen species-activated Erk signaling pathway

Ferruginol induced apoptosis on SK-Mel-28 human malignant melanoma cells mediated through P-p38 and NF-κB

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