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Shintaro Iwasaki, Wakana Iwasaki, Mari Takahashi, Ayako Sakamoto, Chiduru Watanabe, Yuichi Shichino, Stephen N Floor, Koichi Fujiwara, Mari Mito, Kosuke Dodo, Mikiko Sodeoka, Hiroaki Imataka, Teruki Honma, Kaori Fukuzawa, Takuhiro Ito, Nicholas T Ingolia
A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1⋅ATP analog⋅RocA⋅polypurine RNA complex. RocA targets the "bi-molecular cavity" formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA...
December 18, 2018: Molecular Cell
Ancy D Nalli, Lauren E Brown, Cheryl L Thomas, Thomas J Sayers, John A Porco, Curtis J Henrich
Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells...
November 30, 2018: Scientific Reports
Chao Yao, Zhongya Ni, Chenyuan Gong, Xiaowen Zhu, Lixin Wang, Zihang Xu, Chunxian Zhou, Suyun Li, Wuxiong Zhou, Chunpu Zou, Shiguo Zhu
Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell-derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing...
2018: Autophagy
Jie Yang, Bin Li, Qing-Yu He
Prohibitin (PHB) was originally isolated and characterized as an anti-proliferative gene in rat liver. The evolutionarily conserved PHB gene encodes two human protein isoforms with molecular weights of ~33 kDa, PHB1 and PHB2. PHB1 and PHB2 belong to the prohibitin domain family, and both are widely distributed in different cellular compartments such as the mitochondria, nucleus, and cell membrane. Most studies have confirmed differential expression of PHB1 and PHB2 in cancers compared to corresponding normal tissues...
May 21, 2018: Cell Death & Disease
Sunkyu Choi, Aditya M Bhagwat, Rasha Al Mismar, Neha Goswami, Hisham Ben Hamidane, Lu Sun, Johannes Graumann
Cancer metastasis causes approximately 90% of all cancer-related death and independent of the advancement of cancer therapy, a majority of late stage patients suffers from metastatic cancer. Metastasis implies cancer cell migration and invasion throughout the body. Migration requires the formation of pseudopodia in the direction of movement, but a detailed understanding of this process and accordingly strategies of prevention remain elusive. Here, we use quantitative proteomic profiling of human cancer pseudopodia to examine this mechanisms essential to metastasis formation, and identify potential candidates for pharmacological interference with the process...
April 11, 2018: Scientific Reports
Issac Horng Khit Too, Isabelle Bonne, Eng Lee Tan, Justin Jang Hann Chu, Sylvie Alonso
A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system...
January 2018: PLoS Pathogens
Roger G Hall, Ian Bruce, Nigel G Cooke, Louis J Diorazio, Fredrik Cederbaum, Markus R Dobler, Ed Irving
The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi-step syntheses with control of stereochemistry were required to probe the structure-activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper...
December 1, 2017: Chimia
H Yurugi, F Marini, C Weber, K David, Q Zhao, H Binder, L Désaubry, K Rajalingam
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation...
August 17, 2017: Oncogene
Giovanni Benelli, Marimuthu Govindarajan, Sengamalai Senthilmurugan, Periasamy Vijayan, Shine Kadaikunnan, Naiyf S Alharbi, Jamal M Khaled
Mosquitoes threaten the lives of humans, livestock, pets and wildlife around the globe, due to their ability to vector devastating diseases. Aglaia elaeagnoidea, commonly known as Priyangu, is widely employed in Asian traditional medicine and pest control. Medicinal activities include anti-inflammatory, analgesic, anticancer, and anesthetic actions. Flavaglines, six cyclopenta[b]benzofurans, a cyclopenta[bc]benzopyran, a benzo[b]oxepine, and an aromatic butyrolactone showed antifungal properties, and aglaroxin A and rocaglamide were effective to control moth pests...
April 2018: Environmental Science and Pollution Research International
Yin Wu, Marco Giaisi, Rebecca Köhler, Wen-Ming Chen, Peter H Krammer, Min Li-Weber
Multiple myeloma (MM) is an incurable malignancy by the presently known therapies. TRAIL is a promising anticancer agent that virtually not shows any toxicity to normal cells. We have recently carried out clinical trials with a human circularly permuted TRAIL, CPT, against MM saw a partial response in approximate 20-30% of patients. In the current study, we investigated the cause of CPT resistance and revealed that the majority of the MM patients express elevated levels of c-FLIP. Knockdown of c-FLIP expression by siRNA alone was sufficient to increase CPT-mediated apoptosis in a CPT-resistant human MM cell line U266...
March 28, 2017: Cancer Letters
Zhe Zhou, Darryl D Dixon, Anais Jolit, Marcus A Tius
The complex flavagline, (-)-rocaglamide, possesses a synthetically intriguing tricyclic scaffold with five contiguous stereocenters and also exhibits potent anticancer, anti-inflammatory and insecticidal activity. This full account details distinct approaches to (±)- and (-)-rocaglamide utilizing Brønsted acid catalyzed and asymmetric Pd0 -catalyzed Nazarov chemistry developed in our laboratory, respectively. The successful asymmetric synthesis revealed unforeseen mechanistic complexity that required adjusting our strategy to overcome an unanticipated racemization process, an unusual reversible ring-cleavage step and a very facile trialkylsilyl group migration...
October 24, 2016: Chemistry: a European Journal
Michael S Becker, Paul M Müller, Jörg Bajorat, Anne Schroeder, Marco Giaisi, Ehsan Amin, Mohammad R Ahmadian, Oliver Rocks, Rebecca Köhler, Peter H Krammer, Min Li-Weber
Chemotherapy is one of the pillars of anti-cancer therapy. Although chemotherapeutics cause regression of the primary tumor, many chemotherapeutics are often shown to induce or accelerate metastasis formation. Moreover, metastatic tumors are largely resistant against chemotherapy. As more than 90% of cancer patients die due to metastases and not due to primary tumor formation, novel drugs are needed to overcome these shortcomings. In this study, we identified the anticancer phytochemical Rocaglamide (Roc-A) to be an inhibitor of cancer cell migration, a crucial event in metastasis formation...
August 9, 2016: Oncotarget
N A Doudican, S J Orlow
Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma...
January 19, 2017: Oncogene
Shintaro Iwasaki, Stephen N Floor, Nicholas T Ingolia
Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumour cells and repress translation of specific messenger RNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its messenger RNA selectivity is proposed to reflect highly structured 5' untranslated regions that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA...
June 23, 2016: Nature
Ying Huang, Xiang Yang, Tianrui Xu, Qinghong Kong, Yaping Zhang, Yuehai Shen, Yunlin Wei, Guanlin Wang, Kwen-Jen Chang
The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs...
July 2016: International Journal of Oncology
Baochun Wang, Yixiong Li, Fengbo Tan, Zhanxiang Xiao
Pancreatic cancer ranks No.1 in mortality rate worldwide. This study aims to identify the novel anti-pancreatic cancer drugs. Human pancreatic carcinoma cell lines were purchased from ATCC. CPE-based screening assay was used to examine the cell viability. Patient derived tumor xenografts in SCID mice was established. The Caspase-3 and 7 activities were measured using the Caspase Glo 3/7 Assay kit. Soft agar colony formation assay was used to evaluate the colony formation. Wound healing assay was employed to determine the cell migration...
2016: American Journal of Translational Research
Midori A Arai, Yuuki Kofuji, Yuuki Tanaka, Natsuki Yanase, Kazuki Yamaku, Rolly G Fuentes, Utpal Kumar Karmakar, Masami Ishibashi
Rocaglamides are bioactive natural compounds which have a cyclopenta[b]benzofuran core structure. The total synthesis of a reported natural product, 3'-hydroxymethylrocaglate (5), was achieved using [3 + 2] cycloaddition between 3-hydroxyflavone and methyl cinnamate. We also describe the synthesis of rocaglamide heterocycle derivatives and evaluate their Wnt signal inhibitory activities. Compounds 4, 5, 22a, 22b, 22c and 23c showed potent Wnt signal inhibitory activity.
March 21, 2016: Organic & Biomolecular Chemistry
Shufeng Liu, Wenyu Wang, Lauren E Brown, Chao Qiu, Neil Lajkiewicz, Ting Zhao, Jianhua Zhou, John A Porco, Tony T Wang
Identification of novel drug targets and affordable therapeutic agents remains a high priority in the fight against chronic hepatitis C virus (HCV) infection. Here, we report that the cellular proteins prohibitin 1 (PHB1) and 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding step. While predominantly found in mitochondria, PHBs localize to the plasma membrane of hepatocytes through their transmembrane domains and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and inhibited HCV entry at low nanomolar concentrations...
November 2015: EBioMedicine
Ulyana Muñoz Acuña, Jiachen Zi, Jimmy Orjala, Esperanza J Carcache de Blanco
Ambiguine I isonitrile (AmbI) obtained from the cultured cyanobacterium Fischerella ambigua was identified as a potent NF-κB inhibitor (IC50=30 nM). The cytotoxic effect was evaluated in both HT-29 colon cancer cell line (EC50=4.35 μM) and MCF-7 breast cancer cell line (EC50=1.7 μM) using the SRB assay. In the cells treated with AmbI, an increased population of cells was detected in sub G1-phase. The apoptotic effect was associated with block in G1-phase of the cell cycle in treated cells; however, cell death was induced independently of caspase-7...
March 2015: International Journal of Cancer Research
Aiguo Li, Libin Yang, Xiaolin Geng, Xingmei Peng, Tan Lu, Yanjun Deng, Yuzheng Dong
Rheumatoid arthritis is a chronic inflammatory disease that leads to bone and cartilage erosion. The inhibition of osteoblast differentiation by the inflammatory factor TNF-α is critical for the pathogenesis of rheumatoid arthritis. To modulate TNF-α mediated inhibition of osteoblast differentiation is required to improve therapeutic efficacy of rheumatoid arthritis. Here, we explored the potential role of rocaglamide-A, a component of Aglaia plant, in osteoblast differentiation. Rocaglamide-A prevented TNF-α mediated inhibition of osteoblast differentiation, and promoted osteoblast differentiation directly, in both C2C12 and primary mesenchymal stromal cells...
November 2015: Molecules and Cells
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