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Mary J Meegan, Seema Nathwani, Brendan Twamley, Daniela M Zisterer, Niamh M O'Boyle
Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerized when treated with 1...
September 16, 2016: European Journal of Medicinal Chemistry
Fernanda de Lima Moreira, Maísa D Habenschus, Thiago Barth, Lucas M M Marques, Alan Cesar Pilon, Vanderlan da Silva Bolzani, Ricardo Vessecchi, Norberto P Lopes, Anderson R M de Oliveira
Piperlongumine (PPL), a natural plant product, has been extensively studied in cancer treatment going up on clinical trials. Since the first report related to its use on cancer research (in 2011) around 80 papers have been published in less than 10 years, but a gap still remaining. There are no metabolism studies of PPL in human organism. For the lack of a better view, here, the CYP450 in vitro oxidation of PPL was described for the first time. In addition, the enzymatic kinetic data, the predicted in vivo parameters, the produced metabolites, the phenotyping study and possible piperlongumine-drug interactions in vivo is presented...
September 29, 2016: Scientific Reports
Yao Yao, Yueyue Sun, Min Shi, Dandan Xia, Kai Zhao, Lingyu Zeng, Ruosi Yao, Ying Zhang, Zhenyu Li, Mingshan Niu, Kailin Xu
Effective new therapies are urgently needed for the treatment of multiple myeloma (MM), an incurable hematological malignancy. In this study, we evaluated the effects of piperlongumine on MM cell proliferation both in vivo and in vitro. Piperlongumine inhibited the proliferation of MM cells by inducing cell apoptosis and blocking osteoclastogenesis. Notably, piperlongumine also reduced bortezomib resistance in MM cells. In a disseminated MM mouse model, piperlongumine prolonged the survival of tumor-bearing mice without causing any obvious toxicity...
September 13, 2016: Oncotarget
Yi Liao, Xiaojia Niu, Bailing Chen, Holly Edwards, Liping Xu, Chengzhi Xie, Hai Lin, Lisa Polin, Jeffrey W Taub, Yubin Ge, Zhihui Qin
Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1-58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1-58 yielded 3-35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7-C8 olefin of PL obtained 3-31/3-98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells...
September 8, 2016: Journal of Medicinal Chemistry
Genki Tanaka, Ken-Ichi Inoue, Takayuki Shimizu, Kazumi Akimoto, Keiichi Kubota
NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S-transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft-derived spheroids than in fibroblasts. Piperlongumine (2...
September 2016: Cancer Medicine
Merve Alpay, Begum Yurdakok-Dikmen, Gorkem Kismali, Tevhide Sel
AIM OF STUDY: This research indicated to evaluate the effects of piperlongumine (PL), a biologically active alkaloid, and alpha lipoic acid (ALA), a naturally occurring cofactor existed in multienzyme complexes regulating metabolism on leukemia cells. Excessive production of reactive oxygen species (ROS) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies, including acute and chronic myeloid leukemias. The importance of the association between oxidative stress and malignancy is not currently clear; however, there is evidence that tumor...
April 2016: Journal of Cancer Research and Therapeutics
Li-Chen Han, Paul A Stanley, Paul J Wood, Pallavi Sharma, Anchala I Kuruppu, Tracey D Bradshaw, John E Moses
Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation...
August 21, 2016: Organic & Biomolecular Chemistry
Tiago Rodrigues, Florian Sieglitz, Víctor J Somovilla, Pedro M S D Cal, Antony Galione, Francisco Corzana, Gonçalo J L Bernardes
The voltage-dependent L-type Ca(2+) channel was identified as a macromolecular target for (-)-englerin A. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-Englerin A features high substructure dissimilarity to known ligands for voltage-dependent Ca(2+) channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations...
September 5, 2016: Angewandte Chemie
Sahdeo Prasad, Amit K Tyagi
BACKGROUND: Spice and spice-derived compounds have been identified and explored for their health benefits since centuries. One of the spice long pepper has been traditionally used to treat chronic bronchitis, asthma, constipation, gonorrhea, paralysis of the tongue, diarrhea, cholera, malaria, viral hepatitis, respiratory infections, stomach ache, diseases of the spleen, cough, and tumors. METHODS: In this review, the evidences for the chemopreventive and chemotherapeutic potential of piperlongumine have been described...
2016: Current Pharmaceutical Design
Petra Bullova, Antony Cougnoux, Luma Abunimer, Juraj Kopacek, Silvia Pastorekova, Karel Pacak
Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio- and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase (SDHB) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells...
May 26, 2016: Oncotarget
Wen-Jing Yan, Qi Wang, Cui-Hong Yuan, Fu Wang, Yuan Ji, Fang Dai, Xiao-Ling Jin, Bo Zhou
Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS). Considering that ROS generation depends on electrophilicity of PL, PL-CL was designed as its analog by introducing the α-substituent chlorine on the lactam ring to increase moderately its electrophilicity. In comparison with the parent molecule, this molecule was identified as a stronger ROS (O2(∙-) and H2O2) inducer and cytotoxic agent, and manifested more than 15-fold selectivity toward A549 cells over normal WI-38 cells...
August 2016: Free Radical Biology & Medicine
Jie Zheng, Dong Ju Son, Sun Mi Gu, Ju Rang Woo, Young Wan Ham, Hee Pom Lee, Wun Jae Kim, Jae Kyung Jung, Jin Tae Hong
Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0-15 μM) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-κB (NF-κB) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently...
2016: Scientific Reports
Youjun Xiao, Maohua Shi, Qian Qiu, Mingcheng Huang, Shan Zeng, Yaoyao Zou, Zhongping Zhan, Liuqin Liang, Xiuyan Yang, Hanshi Xu
Piperlongumine (PLM) is a natural product from the plant Piper longum that inhibits platelet aggregation, atherosclerosis plaque formation, and tumor cell growth. It has potential value in immunomodulation and the management of autoimmune diseases. In this study, we investigated the role of PLM in regulating the differentiation and maturation of dendritic cells (DCs), a critical regulator of immune tolerance, and evaluated its clinical effects in a rheumatoid arthritis mouse model. We found that PLM treatment reduced LPS-induced murine bone marrow-derived DC maturation, characterized by reduced expression of CD80/86, secretion of MCP-1, IL-12p70, IL-6, TNFα, IFN-γ, and IL-23, and reduced alloproliferation of T cells; however, PLM does not affect cell differentiation...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
San-Yuan Chen, Geng-Hung Liu, Wen-Ying Chao, Chung-Sheng Shi, Ching-Yen Lin, Yun-Ping Lim, Chieh-Hsiang Lu, Peng-Yeh Lai, Hau-Ren Chen, Ying-Ray Lee
Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells...
2016: International Journal of Molecular Sciences
Harsharan Dhillon, Sujan Mamidi, Phillip McClean, Katie M Reindl
Piperlongumine (PL), an alkaloid obtained from long peppers, displays antitumorigenic properties for a variety of human cell- and animal-based models. The aim of this study was to identify the underlying molecular mechanisms for PL anticancer effects on human pancreatic cancer cells. RNA sequencing (RNA-seq) was used to identify the effects of PL on the transcriptome of MIA PaCa-2 human pancreatic cancer cells. PL treatment of pancreatic cancer cells resulted in differential expression of 683 mRNA transcripts with known protein functions, 351 of which were upregulated and 332 of which were downregulated compared to control-treated cells...
June 2016: Journal of Medicinal Food
Jingsong Shi, Song Jiang, Dandan Qiu, Weibo Le, Xiao Wang, Yinhui Lu, Zhihong Liu
OBJECTIVE: To investigate potential drugs for diabetic nephropathy (DN) using whole-genome expression profiles and the Connectivity Map (CMAP). METHODOLOGY: Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs) between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods...
2016: BioMed Research International
Baoji Song, Hongjie Zhan, Quan Bian, Junping Gu
Piperlongumine (PL), a major active component of long peppers, has been reported to possess anti‑cancer properties; however, its effect on gastric cancer (GC) has remained to be demonstrated. The present study assessed the effects of PL on the MKN45 and AGS GC cell lines and explored the underlying mechanisms. An MTT assay revealed that PL suppressed the proliferation of GC cells, while flow cytometric analysis showed that PL inhibited cell cycle progression. Furthermore, Transwell assays revealed the inhibitory effects of PL on the invasion and migration of GC cells...
May 2016: Molecular Medicine Reports
Johann Matschke, Helena Riffkin, Diana Klein, René Handrick, Lutz Lüdemann, Eric Metzen, Tomer Shlomi, Martin Stuschke, Verena Jendrossek
AIMS: Tumor hypoxia is a major biological factor causing poor patient outcome. Evidence is increasing that improved protection against reactive oxygen species (ROS) participates in therapy resistance of chronically hypoxic cancer cells. We aimed at characterizing the relevance of improved ROS defense for radiation resistance of cancer cells with tolerance to cycling anoxia/re-oxygenation stress ("anoxia-tolerant") and at designing rational treatment strategies for overcoming the resulting therapy resistance by targeting the underlying mechanisms identified in an in vitro model...
July 10, 2016: Antioxidants & Redox Signaling
Alhassan Aodah, Aaron Pavlik, Kelly Karlage, Paul B Myrdal
Piperlongumine is a natural alkaloid extracted from piper plants which has been used traditionally for the treatment of certain diseases. This compound shows interesting in vitro pharmacological activity such as selective anticancer activity and higher cytotoxicity than methotrexate, cyclophosphamide and adriamycin on breast, colon, and osteosarcoma cancers, respectively. However, the physicochemical properties for this compound have not been well characterized. In this research, preformulation studies for piperlongumine have been performed to determine factors which influence solubility and stability which, in turn, can be used to assist future formulation development...
2016: PloS One
Peng Zou, Yiqun Xia, Jiansong Ji, Weiqian Chen, Jinsan Zhang, Xi Chen, Vinothkumar Rajamanickam, Gaozhi Chen, Zhe Wang, Lingfeng Chen, Yifeng Wang, Shulin Yang, Guang Liang
Piperlongumine (PL), a natural alkaloid isolated from the fruit of long pepper, is known to selectively kill tumor cells while sparing their normal counterparts. However, the cellular target and potent anticancer efficacy of PL in numerous types of human cancer cells have not been fully defined. We report here that PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells...
May 28, 2016: Cancer Letters
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