Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer

Zou, Peng; Xia, Yiqun; Ji, Jiansong; Chen, Weiqian; Zhang, Jin‐San; Chen, Xi; Rajamanickam, Vinothkumar; Chen, Gaozhi; Wang, Zhe; Chen, Lingfeng; Wang, Yifeng; Yang, Shulin; Liang, Guang

doi:10.1016/j.canlet.2016.02.058

Cited by 118 publications

(89 citation statements)

References 42 publications

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“…Reactive oxygen species (ROS) promote cell survival and growth by regulating cell signaling cascades . However, over production of ROS may lead to oxidative stress and cell apoptosis . In addition, ROS production by cancer cells is triggered by select therapeutic agents and is one of the mechanisms underlying their respective cytotoxicity .…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies found that ROS accumulation is an essential component of the events leading to protein misfolding and ER stress‐induced apoptosis. ROS has also been reported to inhibit the STAT3 pathway leading us to speculate that ROS may be the common upstream mediator of ER stress and STAT3 signaling pathway . STAT3 is a member of a family of latent cytosolic transcription factors that regulate cell proliferation, migration, and differentiation .…”

Section: Discussionmentioning

confidence: 99%

“…25,26 However, over production of ROS may lead to oxidative stress and cell apoptosis. 27,28 In addition, ROS production by cancer cells is triggered by select therapeutic agents and is one of the mechanisms underlying their respective cytotoxicity. 14,28 Based on these findings, we investigated whether intracellular ROS generation was involved in the anti-tumor effects of L48H37.…”

Section: Ros Generation Is the Upstream Regulator Of L48h37-inducedmentioning

confidence: 99%

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Curcumin analog L48H37 induces apoptosis through ROS‐mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells

Chen

Xia

Zou

et al. 2017

Molecular Carcinogenesis

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Lung cancer is the leading cause of cancer-related deaths. Curcumin is a well-known natural product with anticancer ability, however, its poor bioavailability and pharmacokinetic profiles have limited its application in anticancer therapy. Previously, we reported that L48H37, a novel analog of curcumin with higher bioavailability, ameliorated LPS-induced inflammation, but the anticancer effect of L48H37 is still unknown. In the present study, we have investigated the effects of L48H37 in human lung cancer cells. Our results show that L48H37 decreases lung cancer cell growth and colony formation. These alterations were mediated through induction of G2/M cell cycle arrest and apoptosis in lung cancer cells. After L48H37 treatment, ER stress-related proteins were increased, and the expression of p-STAT3 was decreased in a dose-dependent manner. L48H37 also induced the accumulation of ROS in lung cancer cells, and pretreatment with NAC could fully reverse L48H37-induced reactive oxygen species (ROS) increase. Blocking ROS was able to reverse L48H37-induced endoplasmic reticulum (ER) stress, cell cycle arrest, and apoptosis. Finally, we show that L48H37 inhibits the growth of lung cancer xenografts without exhibiting toxicity. Treatment of mice bearing human lung cancer xenografts with L48H37 was also associated with indices of ER stress activation. In summary, our results provide evidence for a novel anti-tumor candidate for the treatment of lung cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ros Generation Is the Upstream Regulator Of L48h37-inducedmentioning

confidence: 99%

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Curcumin analog L48H37 induces apoptosis through ROS‐mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells

Chen

Xia

Zou

et al. 2017

Molecular Carcinogenesis

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“…25 Recently, Liang et al reported that the selenocysteine-containing antioxidant enzyme TrxR1 might be a primary binding target of the piperlongumine. 443 Subsequent studies have revealed that the lactam is critical for the cytotoxicity due to its much stronger electrophile property than that of the α,β -unsaturated double bond, 441 allowing it to react with thiols of the target protein(s). Thus, using ABPP and the design of ABPs ( 154 and 155 ) might be a promising future direction as the strategy for target identification (Scheme 28B).…”

Section: Target Identificationmentioning

confidence: 99%

Chalcone: A Privileged Structure in Medicinal Chemistry

et al. 2017

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Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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“…Therefore, TrxR1 has emerged as a promising biomarker and drug target for oncotherapy. Currently, a substantial body of small molecule inhibitors against TrxR1 has been identified to be potential anti-cancer agents such as metal containing compounds and natural products16171819. Nonetheless, the role of TrxR1 in the onset of breast cancer remains to be elucidated.…”

mentioning

confidence: 99%

Role of thioredoxin reductase 1 in dysplastic transformation of human breast epithelial cells triggered by chronic oxidative stress

Dong

Zhang

Sun

et al. 2016

Sci Rep

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Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme. On the other hand, overexpression of TrxR1 is closely correlated with the initiation of various tumors including breast cancer, though the detailed mechanism remains unclear. Here we investigated the role of TrxR1 in dysplastic transformation of human breast epithelial cell line MCF-10A induced by chronic oxidative stress. Not surprisingly, sustained exposure to H2O2 significantly augmented the expression and activity of TrxR1 in MCF-10A cells. The dysplastically transformed MCF-10A (MCF-10AT) cells undergoing 8-week H2O2 treatment exhibited a certain degree of malignancy in tumorigenicity evaluation. Moreover, TrxR1 inhibitor ethaselen (BBSKE) could partially reverse some malignant phenotypes including epithelial to mesenchymal transition (EMT) of MCF-10AT as well as MCF-7 cells. Collectively, our results supported the considerable involvement of TrxR1 in the onset of breast cancer and BBSKE may be a promising agent against breast cancer.

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Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer

Cited by 118 publications

References 42 publications

Curcumin analog L48H37 induces apoptosis through ROS‐mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells

Curcumin analog L48H37 induces apoptosis through ROS‐mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells

Chalcone: A Privileged Structure in Medicinal Chemistry

Role of thioredoxin reductase 1 in dysplastic transformation of human breast epithelial cells triggered by chronic oxidative stress

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