Piperlongumine Inhibits Akt Phosphorylation to Reverse Resistance to Cisplatin in Human Non-Small Cell Lung Cancer Cells via ROS Regulation

Zhang, Chao; He, Lian‐Jun; Zhu, Yi‐Bao; Fan, Qing-Zhu; Miao, Dong‐Dong; Zhang, Shengpeng; Zhao, Wenying; Li, Xiaoping

doi:10.3389/fphar.2019.01178

Cited by 27 publications

(11 citation statements)

References 42 publications

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“…In line with our data, PIP has been found to reverse chemotherapy resistance in several cancers [60][61][62][63]. Interestingly, a recent study showed PIP to reverse resistance to cisplatin in non-small cell lung cancer cells by inhibiting AKT phosphorylation [64].…”

Section: Discussionsupporting

confidence: 90%

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Machado

Silva

Sousa‐Coelho

et al. 2020

Cancers

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Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.

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Section: Discussionsupporting

confidence: 90%

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Machado

Silva

Sousa‐Coelho

et al. 2020

Cancers

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“…Various doses and values of the IC 50 of the selected alkaloids have been reported in the literature. In the studies provided by Zheng et al and Zhang et al on two types of lung cancer cell lines (A549 and NCI-H460), it was shown that the IC 50 for PL ranged from 13 to 15 µM [36,37]. Similar results were obtained by Wang et al, who confirmed a high cytotoxicity and dose-dependent reduction of A549 survival following a treatment with PL [38].…”

Section: Discussionsupporting

confidence: 65%

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

et al. 2020

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Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the basic life processes of the A549 cell line was considered reasonable. Methods: The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. Results: The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. Conclusion: Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).

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“…29 PL enhanced the tumor-killing effect of traditional chemotherapy and radiotherapy and overcomes drug resistance in human cancer cells. 30,31 Although treatment with PL resulted in cell cycle arrest, the mechanism underlying such a role of PL in CRC cells remains elusive. In the present study, we found that PL dose-dependently suppressed the expression of Cyclin D1 and caused cell cycle G0/G1 arrest in CRC cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Inhibition of ERKs/Akt-Mediated c-Fos Expression Is Required for Piperlongumine-Induced Cyclin D1 Downregulation and Tumor Suppression in Colorectal Cancer Cells</p>

Gao

Zhou

et al. 2020

OTT

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Background: Deregulation of Cyclin D1 and cell cycle progression plays a critical role in tumorigenesis. The natural compound piperlongumine (PL) exhibits potential anticancer effects in various cancer models, but the underlying mechanism needs further elucidation. Methods: The inhibitory effect of PL on colorectal cancer (CRC) cells was determined by anchorage-dependent and-independent assays. The protein level of Cyclin D1 was examined by immunoblot (IB) and immunohistochemical staining (IHC). The mRNA level was determined by qRT-PCR. Phosphorylation of histone H3 was analyzed by immunofluorescence (IF). The cell cycle was examined by flow cytometry. The in vivo antitumor effect was validated by the xenograft mouse model. Results: Cyclin D1 was overexpressed in CRC tissues and cells, and was required for maintaining cell growth, colony formation, and in vivo tumorigenesis. PL decreased the protein level of c-Fos, which eventually reduced the transcriptional activity of AP-1 and the mRNA level of Cyclin D1. Mechanism study showed that PL impaired EGF-induced activation of ERK1/2 and Akt signalings, which resulted in a reduction of c-Fos transcription. Furthermore, PL reduced the half-life of c-Fos and caused the ubiquitination-dependent degradation of c-Fos. Finally, the in vivo antitumor effect of PL on CRC cells was examined using a xenograft mouse model. Conclusion: Our data indicate that PL is a promising antitumor agent that deserves further study for CRC treatment.

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Piperlongumine Inhibits Akt Phosphorylation to Reverse Resistance to Cisplatin in Human Non-Small Cell Lung Cancer Cells via ROS Regulation

Cited by 27 publications

References 42 publications

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

<p>Inhibition of ERKs/Akt-Mediated c-Fos Expression Is Required for Piperlongumine-Induced Cyclin D1 Downregulation and Tumor Suppression in Colorectal Cancer Cells</p>

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