Article
Chemistry, Multidisciplinary
Hyeonwoo Je, Gi-Hoon Nam, Gi Beom Kim, Wonjun Kim, Soo Rin Kim, In-San Kim, Eun Jung Lee
Summary: TRAIL shows promising anti-tumor activity, but faces challenges such as resistance and delivery issues. A nanocage has been developed to efficiently deliver TRAIL and a re-sensitizing drug (DOX) to overcome TRAIL-resistant tumors, demonstrating potential as an effective antitumor agent.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Pharmacology & Pharmacy
Yu Ren, Xue Wang, Shuaishuai Huang, Yangkai Xu, Guobin Weng, Rui Yu
Summary: In this study, we found that alternol sensitized renal carcinoma cells to TRAIL-induced apoptosis by inhibiting antiapoptotic proteins, upregulating DR5 levels, ROS generation, and the CHOP pathway, thus enhancing TRAIL-mediated apoptosis.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Oncology
K. M. A. Zinnah, Sang-Youel Park
Summary: The study demonstrated the mechanism behind the synergistic anticancer effect of amitriptyline and TRAIL, showing that amitriptyline increases TRAIL-induced apoptosis by upregulating death receptors DR4 and DR5. Inhibition of autophagy by amitriptyline was also shown to enhance DR4 and DR5 expression.
Review
Biochemistry & Molecular Biology
Anderson Luiz-Ferreira, Teresa Pacifico, Alefe Cardoso Cruz, Federica Laudisi, Giovanni Monteleone, Carmine Stolfi
Summary: TRAIL is a promising anticancer agent that selectively induces apoptosis in transformed cells, while flavonoids, natural compounds found in plants, have shown competence in enhancing TRAIL-induced apoptosis. However, bioavailability issues are the main limitations for the clinical use of flavonoids.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Yang Cao, Ying He, Litao Yang, Zhou Luan
Summary: Studies have shown that CR-31 treatment can counter the resistance to TRAIL in GBC cells, increase sensitivity to apoptosis, and may serve as a novel therapeutic strategy.
Article
Chemistry, Multidisciplinary
Tianshan She, Fen Yang, Shiyuan Chen, Hao Yang, Ze Tao, Huimin Xing, Jie Chen, Huansheng Chang, Hongyu Lu, Tao Su, Youmei Jin, Yi Zhong, Jingqiu Cheng, Hong Zhu, Xiaofeng Lu
Summary: The clinical application of TRAIL is limited by its inefficient induction of apoptosis in tumor cells. Superglue-mediated hyperoligomerization of TRAIL can increase its valency and improve its efficacy. In this study, minimal superglue peptide pairs were fused to the TRAIL promoter to create superglue-fusion TRAIL variants. These variants showed high expression and trimerization similar to native TRAIL. With the help of Snoopligase or SpyStapler, these variants could be crosslinked into hexavalent TRAIL variants. The hexavalent SnHexaTR variant produced by Snoopligase showed the highest yield and exhibited 10-40 times greater cytotoxicity than native TRAIL in tumor cells. It also had a longer half-life and greater tumor uptake, leading to the eradication of tumor xenografts. Hexavalent SnHexaTR, as a novel anticancer agent candidate, has great potential for clinical application in cancer therapy.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Medicine, Research & Experimental
Milad Ashrafizadeh, Sepideh Mirzaei, Kiavash Hushmandi, Vahid Rahmanian, Amirhossein Zabolian, Mehdi Raei, Mahdi Vasheghani Farahani, Mohammad Ali Sheikh Beig Goharrizi, Haroon Khan, Ali Zarrabi, Saeed Samarghandian
Summary: Lung cancer is a major cause of death worldwide, with various risk factors such as genetics, epigenetics, and environmental factors playing a role in its development. The AMP-activated protein kinase (AMPK) signaling pathway is crucial in lung cancer progression, influencing metastasis, proliferation, and response to treatments like chemotherapy and radiotherapy. AMPK activation can both enhance and suppress lung cancer progression, indicating its complex and dual role in cancer cells.
Article
Engineering, Biomedical
Hao Yang, Heng Li, Fen Yang, Ze Tao, Qiuxiao Shi, Tianshan She, Yanru Feng, Zhao Li, Jie Chen, Yi Zhong, Tao Su, Wengjuan Zeng, Yong Zhang, Shisheng Wang, Lan Li, Tingting Long, Dan Long, Jingqiu Cheng, Hong Zhu, Xiaofeng Lu
Summary: Increasing the valency of death receptor agonist by promoting higher-order receptor clustering is an efficient way to induce tumor cell apoptosis. However, currently available strategies to improve the clustering ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) often result in large proteins with poor tumor penetration. In this study, we demonstrate that covalent protein ligation using small molecular superglues can assemble higher-order TRAIL variants, leading to significantly increased apoptosis induction in vitro and in vivo.
Review
Oncology
Hojjat Alizadeh Zeinabad, Eva Szegezdi
Summary: TRAIL, as a promising anticancer drug with low toxicity, has not been successfully translated into a therapeutic molecule due to its short in vivo half-life and tumor cells' resistance. Nanotechnology shows potential to overcome these limitations and offers better solutions.
Review
Biochemistry & Molecular Biology
Bingyu Sun, Yongqiang Liu, Danhua He, Jinke Li, Jiawei Wang, Wulin Wen, Ming Hong
Summary: Current chemotherapy agents have severe cytotoxicity to normal cells, resulting in decreased quality of life. Traditional Chinese medicine ingredients have shown potential to sensitize tumor cells to TRAIL-induced apoptosis, offering new insights for cancer treatment.
JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B
(2021)
Article
Biochemistry & Molecular Biology
So Rae Song, Seung Un Seo, Seon Min Woo, Ji Yun Yoon, Simmyung Yook, Taeg Kyu Kwon
Summary: In this study, the research focused on the effect of traditional Chinese medicinal herb, Tubeimoside-1 (TBMS-1), on the sensitization of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The results showed that combination therapy using TBMS-1 and TRAIL increased apoptotic cell death. Mechanistically, TBMS-1 destabilized c-FLIP expression by downregulating STAMBPL1, a deubiquitinase (DUB). Moreover, knockdown of STAMBPL1 enhanced TRAIL-mediated apoptosis via c-FLIP downregulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Immunology
Ehsan Razeghian, Wanich Suksatan, Heshu Sulaiman Rahman, Dmitry O. Bokov, Walid Kamal Abdelbasset, Ali Hassanzadeh, Faroogh Marofi, Mahboubeh Yazdanifar, Mostafa Jarahian
Summary: TRAIL, as an immune cytokine, has the ability to selectively eliminate tumor cells but faces resistance issues. Studies have shown that overcoming TRAIL resistance can be achieved through combined treatment with other antitumor agents, the utilization of human MSCs and NPs for TRAIL delivery. These approaches show promise in enhancing the therapeutic efficacy and survival rate in cancer treatment.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Medicine, Research & Experimental
Tianshan She, Qiuxiao Shi, Zhao Li, Yanru Feng, Hao Yang, Ze Tao, Heng Li, Jie Chen, Shisheng Wang, Yan Liang, Jingqiu Cheng, Xiaofeng Lu
Summary: Chemotherapeutic multidrug resistance (MDR) and TRAIL resistance are common in colorectal cancer (CRC) cells. Combination therapy of long-acting TRAIL and tumor-cell targeted photodynamic therapy (PDT) shows promising results in combating CRC with both types of resistance.
Article
Oncology
Shihai Liu, Jing Qiu, Guifang He, Weitai He, Changchang Liu, Duo Cai, Huazheng Pan
Summary: The interaction between TRAIL and IER3 can induce apoptotic death of HCC cells and inhibit their proliferation and migration by inhibiting Wnt/beta-catenin signaling. This TRAIL/IER3/beta-catenin axis may serve as a viable therapeutic target for HCC patients.
CANCER CELL INTERNATIONAL
(2021)
Review
Biochemistry & Molecular Biology
Longfei Deng, Xuan Zhai, Ping Liang, Hongjuan Cui
Summary: TRAIL holds therapeutic potential in cancer treatment, but many cancers, including GBM, exhibit resistance. Recent studies have identified new mechanisms in regulating TRAIL-induced apoptosis in GBM and effective combinatorial strategies. The TRAIL/TRAIL death receptor axis may have future clinical applications for GBM treatment.
Article
Cardiac & Cardiovascular Systems
Anusha Seneviratne, Luke Cave, Gareth Hyde, Soren Kragh Moestrup, David Carling, Justin C. Mason, Dorian O. Haskard, Joseph James Boyle
Summary: Metformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, resulting in highly suppressed atherogenesis in hyperlipidaemic mice via haematopoietic AMPK.
CARDIOVASCULAR RESEARCH
(2021)
Article
Gastroenterology & Hepatology
Suhrid Banskota, Huaqing Wang, Yun Han Kwon, Jaya Gautam, Pallavi Gurung, Sabah Haq, F. M. Nazmul Hassan, Dawn M. Bowdish, Jung-Ae Kim, David Carling, Morgan D. Fullerton, Gregory R. Steinberg, Waliul Khan
Summary: Genetic deletion of AMPK beta 1 in macrophages upregulates proinflammatory cytokine production, exacerbates dextran sodium sulfate-induced colitis severity in mice, increases nuclear translocation of nuclear factor-kappa B, and impairs autophagy both in vitro and in vivo. Additionally, commonly used anti-inflammatory drugs such as 5-aminosalicylic acid (mesalazine) and sodium salicylate ameliorate dextran sodium sulfate-induced colitis by activating macrophage AMPK targeting the beta 1 subunit.
INFLAMMATORY BOWEL DISEASES
(2021)
Article
Cell Biology
Rocio Mora-Molina, Daniela Stoehr, Markus Rehm, Abelardo Lopez-Rivas
Summary: Protein misfolding or unfolding and the resulting endoplasmic reticulum stress commonly occur in highly proliferative tumors. The role of caspase-8 inhibitor cFLIP in regulating the balance between apoptosis and survival in colon cancer cells undergoing ER stress has been investigated. Maintaining high cFLIP levels during ER stress can inhibit caspase-8 activation and apoptosis, while cFLIP knockdown accelerates caspase-8 activation and apoptosis during ER stress. The resistance of multicellular tumor spheroids to ER stress-induced apoptosis correlates with sustained cFLIP(L) expression.
CELL DEATH & DISEASE
(2022)
Article
Endocrinology & Metabolism
Marie-Sophie Nguyen-Tu, Joseph Harris, Aida Martinez-Sanchez, Pauline Chabosseau, Ming Hu, Eleni Georgiadou, Alice Pollard, Pablo Otero, Livia Lopez-Noriega, Isabelle Leclerc, Kei Sakamoto, Dieter Schmoll, David M. Smith, David Carling, Guy A. Rutter
Summary: The role of AMP-activated protein kinase (AMPK) in the control of insulin secretion is still debatable. AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators.
Article
Multidisciplinary Sciences
Anke Nijhuis, Arti Sikka, Orli Yogev, Lili Herendi, Cristina Balcells, Yurui Ma, Evon Poon, Clare Eckold, Gabriel N. Valbuena, Yuewei Xu, Yusong Liu, Barbara Martins da Costa, Michael Gruet, Chiharu Wickremesinghe, Adrian Benito, Holger Kramer, Alex Montoya, David Carling, Elizabeth J. Want, Yann Jamin, Louis Chesler, Hector C. Keun
Summary: This study demonstrates that high-risk neuroblastoma is sensitive to indisulam, a drug that targets both RNA splicing and cellular metabolism. The researchers show that indisulam induces the loss of RBM39, accumulation of splicing errors, and growth inhibition in neuroblastoma models. Analysis of RNA sequencing and metabolic profiling data reveals disruptions to cell cycle and metabolism in response to indisulam. The authors also demonstrate complete tumor regression without relapse in mice models treated with indisulam, confirming the therapeutic potential of targeting both metabolism and RNA splicing in high-risk neuroblastoma.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Rocio Mora-Molina, Abelardo Lopez-Rivas
Summary: This review article discusses the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress, with a focus on the role of TRAIL-R2/DR5 in the apoptotic process and the mechanisms controlling FLIP levels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Anissa A. Widjaja, Sivakumar Viswanathan, Joyce Goh Wei Ting, Jessie Tan, Shamini G. Shekeran, David Carling, Wei-Wen Lim, Stuart A. Cook
Summary: IL11 activates fibroblasts and causes epithelial cell dysfunction through the IL11/mTOR axis. The activation of ERK/P90RSK by IL11 leads to the phosphorylation and inactivation of LKB1, inhibiting AMPK and activating mTOR. Inhibiting IL11 activity or stimulating AMPK can reverse the IL11-induced phenotypes in different cell types.
Article
Cell Biology
Rosario Yerbes, Rocio Mora-Molina, F. Javier Fernandez-Farran, Laura Hiraldo, Abelardo Lopez-Rivas, Carmen Palacios
Summary: This study reveals a previously unknown cell death mechanism triggered in glutamine-addicted tumor cells in response to glutamine metabolism limitation. The mechanism is regulated by GCN2 activation induced by glutamine starvation and involves the activation of the extrinsic apoptotic pathway mediated by TRAIL-R2.
CELL DEATH & DISEASE
(2022)
Article
Endocrinology & Metabolism
Emma Rose McGlone, T. Bertie Ansell, Cecilia Dunsterville, Wanling Song, David Carling, Alejandra Tomas, Stephen R. Bloom, Mark S. P. Sansom, Tricia Tan, Ben Jones
Summary: The study found that cellular cholesterol levels influence the signaling and glucose metabolism of glucagon receptors, and the use of simvastatin in a high cholesterol environment can improve this situation.
MOLECULAR METABOLISM
(2022)
Article
Cell Biology
David C. D. Hope, Charlotte E. Hinds, Tatiana Lopes, Matthew L. Vincent, Jed V. Shrewsbury, Arthur T. C. Yu, Iona Davies, Rebecca Scott, Ben Jones, Kevin G. Murphy, James S. Minnion, Alessandro Sardini, David Carling, Thomas A. Lutz, Stephen R. Bloom, Tricia M. M. Tan, Bryn M. Owen
Summary: Glucagon analogs have potential in the development of next-generation anti-obesity therapeutics. This study shows that the weight loss induced by a long-acting glucagon analog, G108, is linked to hypoaminoacidemia, which is associated with the amino acid catabolic action of glucagon. Low plasma amino acids are necessary for the energy expenditure and weight loss mediated by G108. Additionally, dietary protein supplementation does not affect the glycemic and hepatic steatosis-improving abilities of G108 in obese mice.
CELL REPORTS MEDICINE
(2022)
Article
Oncology
Theodora A. Constantin, Anabel Varela-Carver, Kyle K. Greenland, Gilberto Serrano de Almeida, Ellen Olden, Lucy Penfold, Simon Ang, Alice Ormrod, Damien A. Leach, Chun-Fui Lai, Edward K. Ainscow, Ash K. Bahl, David Carling, Matthew J. Fuchter, Simak Ali, Charlotte L. Bevan
Summary: This study demonstrates that the CDK7 inhibitor CT7001 selectively inhibits proliferation and cell cycle in prostate cancer cells, and exerts antitumor effects by activating p53, inducing apoptosis, and suppressing transcription mediated by full-length and constitutively active AR splice variants. Oral administration of CT7001 suppresses the growth of CRPC xenografts, and significantly enhances the growth inhibition achieved by enzalutamide. Transcriptome analyses indicate that the mode of action of CT7001 in vivo is through inhibition of the cell cycle and AR function.
BRITISH JOURNAL OF CANCER
(2023)
Article
Gastroenterology & Hepatology
Emma Rose McGlone, Matthieu Siebert, Marian Dore, David C. D. Hope, Iona Davies, Bryn Owen, Bernard Khoo, Rob Goldin, Dave Carling, Stephen Bloom, Maude Le Gall, Tricia M-M. Tan
Summary: The study investigated the effects of sleeve gastrectomy on weight-independent improvements in liver steatosis in mice with diet-induced obesity. It was found that VSG not only improves liver fat content but also enhances insulin and glucagon sensitivity.
LIVER INTERNATIONAL
(2023)
Article
Cell Biology
Lucy Penfold, Angela Woods, Alice E. Pollard, Julia Arizanova, Eneko Pascual-Navarro, Phillip J. Muckett, Marian H. Dore, Alex Montoya, Chad Whilding, Louise Fets, Joao Mokochinski, Theodora A. Constantin, Anabel Varela-Carver, Damien A. Leach, Charlotte L. Bevan, Alexander Yu. Niktin, Zoe Hall, David Carling
Summary: Emerging evidence suggests that metabolic dysregulation is a driver of prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK), a master regulator of metabolism, has a protective effect on PCa progression in vivo. AMPK activation induces the expression of PGC1a, leading to catabolic metabolic reprogramming in PCa cells. This reprogramming inhibits PCa disease progression and is associated with the inhibition of a gene network involved in cell cycle regulation.
Meeting Abstract
Rheumatology
Lida Kabir, Robert Maughan, Koralia Paschalaki, Anna Randi, David Carling, Deepa Arachchillage, Justin Mason, Charis Pericleous
ARTHRITIS & RHEUMATOLOGY
(2022)
Article
Gastroenterology & Hepatology
Pascale Gluais-Dagorn, Marc Foretz, Gregory R. Steinberg, Battsetseg Batchuluun, Anna Zawistowska-Deniziak, Joost M. Lambooij, Bruno Guigas, David Carling, Pierre-Axel Monternier, David E. Moller, Sebastien Bolze, Sophie Hallakou-Bozec
Summary: The study demonstrates that direct activation of AMPK can improve all core components of NASH and alleviate related hyperglycemia, dyslipidemia, and systemic inflammation. Additionally, novel properties of direct AMPK activation were revealed, including improved insulin resistance and direct suppression of inflammation and fibrogenesis. These findings suggest the potential for direct AMPK activation as an effective treatment for patients with NASH, with effects also observed in human cells.
HEPATOLOGY COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Paola Orlandi, Marta Banchi, Francesca Vaglini, Marco Carli, Stefano Aringhieri, Arianna Bandini, Carla Pardini, Cristina Viaggi, Michele Lai, Greta Ali, Alessandra Ottani, Eleonora Vandini, Patrizia Guidi, Margherita Bernardeschi, Veronica La Rocca, Giulio Francia, Gabriella Fontanini, Mauro Pistello, Giada Frenzilli, Daniela Giuliani, Marco Scarselli, Guido Bocci
Summary: This study investigates the role of MC4R in melanoma and the use of the selective antagonist ML in combination with vemurafenib. The results show that ML can inhibit melanoma cell proliferation and induce apoptosis through the inhibition of ERK1/2 phosphorylation and reduction of BCL-XL expression. The combination of vemurafenib and ML exhibits a synergistic effect in vitro and inhibits tumor growth in vivo without causing adverse effects.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Conor J. Bloxham, Katina D. Hulme, Fabrizio Fierro, Christian Fercher, Cassandra L. Pegg, Shannon L. O'Brien, Simon R. Foster, Kirsty R. Short, Sebastian G. B. Furness, Melissa E. Reichelt, Masha Y. Niv, Walter G. Thomas
Summary: Bitter taste receptors (T2Rs) are a type of G protein-coupled receptors that allow humans to detect aversive and toxic substances. This study characterized the functional properties of previously identified T2Rs in human cardiac tissues and their naturally occurring polymorphisms. The results showed differences in signaling among different T2R variants, and revealed a potential association between the T2R50 Tyr203 variant and cardiovascular disease.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Lu Chen, Huanying Shi, Wenxin Zhang, Yongjun Zhu, Haifei Chen, Zimei Wu, Huijie Qi, Jiafeng Liu, Mingkang Zhong, Xiaojin Shi, Tianxiao Wang, Qunyi Li
Summary: This study demonstrates that Carfilzomib exhibits potent anti-tumor activity against esophageal squamous cell carcinoma (ESCC) by triggering mitochondrial apoptosis and reprogramming cellular metabolism. It has been identified that activating transcription factor 3 (ATF3) plays a crucial role as a cellular target in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively counteracts the effects of Carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, ATF3 mediates the anti-tumor activity of Carfilzomib, suggesting its potential as a therapeutic agent for ESCC.
BIOCHEMICAL PHARMACOLOGY
(2024)
Review
Pharmacology & Pharmacy
Xing Zhang, Xiang Li, Ran Xia, Hong-Sheng Zhang
Summary: This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer and highlights the role of redox status and metabolism. Combination therapy for ferroptosis has great potential in treating resistant malignant tumors.
BIOCHEMICAL PHARMACOLOGY
(2024)