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Hara MA, Ramadan M, Abdelhameid MK, Taher ES, Mohamed KO. Pyroptosis and chemical classification of pyroptotic agents. Mol Divers 2025; 29:2765-2782. [PMID: 39316325 PMCID: PMC12081555 DOI: 10.1007/s11030-024-10987-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.
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Affiliation(s)
- Mohammed A Hara
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al Azhar University (Assiut), Assiut, 71524, Egypt
| | - Mohamed Ramadan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al Azhar University (Assiut), Assiut, 71524, Egypt.
| | - Mohammed K Abdelhameid
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ehab S Taher
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al Azhar University (Assiut), Assiut, 71524, Egypt
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan
| | - Khaled O Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sinai University (Arish Branch), ElArich, Egypt
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2
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Wang H, Zhang G, Zhao C, Xue Y, Zhu D, Chang Y. RORγt agonist LYC-55716 potentiates IFN-α's efficacy in hepatocellular carcinoma through enhancing cytotoxicity of Tc17 cells and infiltration of CD8 + T cells. Biochem Pharmacol 2025; 238:116963. [PMID: 40312017 DOI: 10.1016/j.bcp.2025.116963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/13/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
While interferon-alpha (IFN-α) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-α resistance and improve its efficacy. RAR-related orphan receptor gamma t (RORγt) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the RORγt agonist-LYC-55716 and IFN-α significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8+ T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8+ T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy.
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Affiliation(s)
- Heng Wang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; Shanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | | | - Cai Zhao
- Sunshine Lake Pharma Co., Ltd., Dongguan 523871, China
| | - Youan Xue
- Sunshine Lake Pharma Co., Ltd., Dongguan 523871, China
| | - Di Zhu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai 201100, China; Shandong Academy of Pharmaceutical Science, Jinan 250101, China; Fudan University Shanghai Cancer Center, Shanghai 200032, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, and Department of Oncology, Second Affiliated Hospital of Guilin Medical University, China.
| | - Yan Chang
- Shanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
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3
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Tomatsu S, Abbott SM, Attarian H. Clinical Chronobiology: Circadian Rhythms in Health and Disease. Semin Neurol 2025. [PMID: 39961369 DOI: 10.1055/a-2538-3259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2025]
Abstract
Circadian rhythms (CRs) are entrainable endogenous rhythms that respond to external stimuli and regulate physiological functions. The suprachiasmatic nucleus (SCN) in the hypothalamus is the mammalian master clock that synchronizes all other tissue-specific peripheral clocks, primarily through gamma-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP). The SCN follows Earth's 24-hour cycle by light entrainment through the retinohypothalamic tract. At the cellular level, the core clock genes CLOCK, BMAL1, PER1-PER3, CRY1, and CRY2 regulate CRs in a negative feedback loop. The circadian disruption of the sleep-wake cycle manifests in at least six distinct clinical conditions. These are the circadian rhythm sleep-wake disorders (CRSWDs). Their diagnosis is made by history, sleep diaries, and actigraphy. Treatment involves a combination of timed light exposure, melatonin/melatonin agonists, and behavioral interventions. In addition, CR disturbances and subsequent misalignment can increase the risk of a variety of illnesses. These include infertility and menstrual irregularities as well as diabetes, obesity, fatty liver disease, and other metabolic syndromes. In addition, a disruption in the gut microbiome creates a proinflammatory environment. CR disturbances increase the risk for mood disorders, hence the utility of light-based therapies in depression. People with neurodegenerative disorders demonstrate significant disturbances in their CRs, and in their sleep-wake cycles. Circadian realignment therapies can also help decrease the symptomatic burden of these disorders. Certain epilepsy syndromes, such as juvenile myoclonic epilepsy (JME), have a circadian pattern of seizures. Circadian disturbances in epilepsy can be both the consequence and cause for breakthrough seizures. The immune system has its own CR. Disturbances in these due to shift work, for instance, can increase the risk of infections. CR disturbances can also increase the risk of cancer by impacting DNA repair, apoptosis, immune surveillance, and cell cycle regulation. Moreover, the timing of chemotherapeutic agents has been shown to increase their therapeutic impact in certain cancers.
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Affiliation(s)
- Shizuka Tomatsu
- Department of Neurology, Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Sabra M Abbott
- Department of Neurology, Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Hrayr Attarian
- Department of Neurology, Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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4
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Karaś K, Pastwińska J, Sałkowska A, Karwaciak I, Bachorz RA, Ratajewski M. The cyclin-dependent kinase inhibitor AT7519 is a human RORγt agonist. Immunol Cell Biol 2025; 103:317-327. [PMID: 39853787 DOI: 10.1111/imcb.12851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/18/2024] [Accepted: 01/05/2025] [Indexed: 01/26/2025]
Abstract
AT7519, which inhibits multiple cyclin-dependent kinases, has been extensively investigated in various types of cancer cells. Previous studies have demonstrated the ability of this molecule to suppress the expression of the nuclear receptor retinoic acid-related orphan receptor gamma (RORγ) and several genes involved in hepatocellular carcinoma progression. In this study, we identified a distinct agonistic effect of AT7519 on RORγt, an isoform expressed by various immune cells, including T helper 17 lymphocytes. These immune cells play pivotal roles in shaping the tumor microenvironment and promoting the anticancer response of the immune system. After exposure to AT7519 during differentiation, primary human CD4+ T cells presented increased expression of IL17A/F, IFNG and GZMB and decreased expression of PDCD1 and CTLA4. These findings elucidate a previously unrecognized facet of AT7519 activity and suggest the potential incorporation of this molecule into immune therapies to augment the effectiveness of diverse anticancer strategies involving anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) regimens.
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Affiliation(s)
- Kaja Karaś
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
| | - Joanna Pastwińska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
| | - Anna Sałkowska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
| | - Iwona Karwaciak
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
| | - Rafał A Bachorz
- Laboratory of Molecular Modeling, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
| | - Marcin Ratajewski
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland
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Biagioli M, Di Giorgio C, Massa C, Marchianò S, Bellini R, Bordoni M, Urbani G, Roselli R, Lachi G, Morretta E, Piaz FD, Charlier B, Fiorillo B, Catalanotti B, Cari L, Nocentini G, Ricci P, Distrutti E, Festa C, Sepe V, Zampella A, Monti MC, Fiorucci S. Microbial-derived bile acid reverses inflammation in IBD via GPBAR1 agonism and RORγt inverse agonism. Biomed Pharmacother 2024; 181:117731. [PMID: 39657506 DOI: 10.1016/j.biopha.2024.117731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 12/12/2024] Open
Abstract
The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Bar Pharmaceuticals s.r.l., Via Gramsci 88/A, Reggio Emilia 42124, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Ginevra Lachi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Fabrizio Dal Piaz
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
| | - Bruno Charlier
- University hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy
| | - Bianca Fiorillo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Luigi Cari
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Nocentini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Festa
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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Karwaciak I, Pastwińska J, Sałkowska A, Bachorz RA, Ratajewski M. Evaluation of the activity of cardiac glycosides on RORγ and RORγT nuclear receptors. Arch Biochem Biophys 2024; 759:110085. [PMID: 38971421 DOI: 10.1016/j.abb.2024.110085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Cardiac glycosides, derived from plants and animals, have been recognized since ancient times. These substances hinder the function of the sodium-potassium pump within eukaryotic cells. Many reports have shown that these compounds influence the activity of nuclear receptors. Thus, we assessed the effects of various cardiac glycosides at nontoxic concentrations on RORγ and RORγT. RORγT is a crucial protein involved in the differentiation of Th17 lymphocytes. Sixteen analyzed cardiac glycosides exhibited varying toxicities in HepG2 cells, all of which demonstrated agonistic effects on RORγ, as confirmed in the RORγ-HepG2 reporter cell line. The overexpression of both the RORγ and RORγT isoforms intensified the effects of these compounds. Additionally, these glycosides induced the expression of G6PC, a gene regulated by RORγ, in HepG2 cells. Subsequently, the effects of two endogenous cardiac glycosides (marinobufagenin and ouabain) and the three most potent glycosides (bufalin, oleandrin, and telecinobufagenin) were evaluated in Th17 primary lymphocytes. All of these compounds increased the expression of the IL17A, IL17F, IFNG, and CXCL10 genes, but they exhibited varying effects on GZMB and CCL20 expression. Molecular docking analysis revealed the robust binding affinity of cardiac glycosides for the ligand binding domain of the RORγ/RORγT receptors. Thus, we demonstrated that at nontoxic concentrations, cardiac glycosides have agonistic effects on RORγ/RORγT nuclear receptors, augmenting their activity. This potential can be harnessed to modulate the phenotype of IL17-expressing cells (e.g., Th17 or Tc17 lymphocytes) in adoptive therapy for combating various types of cancer.
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Affiliation(s)
- Iwona Karwaciak
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, 93-232, Lodz, Poland
| | - Joanna Pastwińska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, 93-232, Lodz, Poland
| | - Anna Sałkowska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, 93-232, Lodz, Poland
| | - Rafał A Bachorz
- Laboratory of Molecular Modeling, Institute of Medical Biology, Polish Academy of Sciences, 93-232, Lodz, Poland
| | - Marcin Ratajewski
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, 93-232, Lodz, Poland.
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Wang Z, Ma L, Meng Y, Fang J, Xu D, Lu Z. The interplay of the circadian clock and metabolic tumorigenesis. Trends Cell Biol 2024; 34:742-755. [PMID: 38061936 DOI: 10.1016/j.tcb.2023.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/09/2023] [Accepted: 11/09/2023] [Indexed: 09/08/2024]
Abstract
The circadian clock and cell metabolism are both dysregulated in cancer cells through intrinsic cell-autonomous mechanisms and external influences from the tumor microenvironment. The intricate interplay between the circadian clock and cancer cell metabolism exerts control over various metabolic processes, including aerobic glycolysis, de novo nucleotide synthesis, glutamine and protein metabolism, lipid metabolism, mitochondrial metabolism, and redox homeostasis in cancer cells. Importantly, oncogenic signaling can confer a moonlighting function on core clock genes, effectively reshaping cellular metabolism to fuel cancer cell proliferation and drive tumor growth. These interwoven regulatory mechanisms constitute a distinctive feature of cancer cell metabolism.
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Affiliation(s)
- Zheng Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China
| | - Leina Ma
- Department of Oncology, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong 266003, China
| | - Ying Meng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China
| | - Jing Fang
- Department of Oncology, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong 266003, China.
| | - Daqian Xu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
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Savvidis C, Kallistrou E, Kouroglou E, Dionysopoulou S, Gavriiloglou G, Ragia D, Tsiama V, Proikaki S, Belis K, Ilias I. Circadian rhythm disruption and endocrine-related tumors. World J Clin Oncol 2024; 15:818-834. [PMID: 39071458 PMCID: PMC11271730 DOI: 10.5306/wjco.v15.i7.818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.
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Affiliation(s)
- Christos Savvidis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Efthymia Kallistrou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Eleni Kouroglou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Sofia Dionysopoulou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | | | - Dimitra Ragia
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Vasiliki Tsiama
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Stella Proikaki
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Konstantinos Belis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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10
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Wang Y, Narasimamurthy R, Qu M, Shi N, Guo H, Xue Y, Barker N. Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis. NATURE CANCER 2024; 5:546-556. [PMID: 38654103 DOI: 10.1038/s43018-024-00759-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/07/2024] [Indexed: 04/25/2024]
Abstract
The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.
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Affiliation(s)
- Yu Wang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rajesh Narasimamurthy
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Meng Qu
- The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Nuolin Shi
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haidong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Yuezhen Xue
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
| | - Nick Barker
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Baindara P. Targeting interleukin-17 in radiation-induced toxicity and cancer progression. Cytokine Growth Factor Rev 2024; 75:31-39. [PMID: 38242827 DOI: 10.1016/j.cytogfr.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/03/2024] [Indexed: 01/21/2024]
Abstract
Recent strategies to combine chemoradiation with immunotherapy to treat locally advanced lung cancer have improved five-year survival outcomes. However, collateral toxicity to healthy lungs, esophagus, cardiac, and vascular tissue continues to limit the effectiveness of curative-intent thoracic radiation (tRT). It is necessary to gain a deeper comprehension of the fundamental mechanisms underlying inflammation-mediated radiation-induced damage to normal cells. Several cells have been linked in published studies to the release of cytokines and chemokines after radiation therapy. Several inflammatory mediators, such as IL-1, IL-6, TNF-α, and TGF-β, also cause the production of Interleukin-17 (IL-17), a cytokine that is essential for maintaining immunological homeostasis and plays a role in the toxicity caused by radiation therapy. However, currently, the role of IL-17 in RT-induced toxicity in conjunction with cancer progression remains poorly understood. This review provides an overview of the most recent data from the literature implicating IL-17 in radiation-mediated tissue injuries and the efficacy of tRT in lung cancer, as well as its potential as a therapeutic target for interventions to reduce the side effects of tRT with curative intent and to boost an anti-tumor immune response to improve treatment outcomes. IL-17 may also act as a biomarker for predicting the effectiveness of a given treatment as well as the toxicity caused by tRT.
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Affiliation(s)
- Piyush Baindara
- Radiation Oncology, School of Medicine, NextGen Precision Health, University of Missouri, Columbia 65211, United States.
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12
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Khan IA, Singh N, Gunjan D, Dash NR, Nayak B, Gupta S, Saraya A. Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma. Hum Immunol 2024; 85:110748. [PMID: 38177009 DOI: 10.1016/j.humimm.2023.110748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/12/2023] [Accepted: 12/29/2023] [Indexed: 01/06/2024]
Abstract
AIM Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.
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Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India.
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13
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Lu L, Huang Y, Song M, Sun N, Xia L, Yu M, Zhao M, Qiu R, Chen JA, Zhao Y, Wang H, Guo H, Li Y, Zhu D, Wang Y, Xie Q. Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy. J Med Chem 2023; 66:16091-16108. [PMID: 37982494 DOI: 10.1021/acs.jmedchem.3c01492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
The master transcription factor receptor retinoic acid receptor-related orphan receptor γt (RORγt) regulates the differentiation of T-helper 17 (Th17) cells and the production of interleukin-17 (IL-17). Activation of RORγt+ T cells in the tumor microenvironment promotes immune infiltration to more effectively inhibit tumor growth. Therefore, RORγt agonists provide a reachable approach to cancer immunotherapy. Herein, a series of biaryl amide derivatives as novel RORγt agonists were designed, synthesized, and evaluated. Starting from the reported RORγt inverse agonist GSK805 (1), "functionality switching" and structure-based drug optimization led to the discovery of a promising RORγt agonist lead compound 14, which displayed potent and selective RORγt agonist activity and significantly improved metabolic stability. With excellent in vivo pharmacokinetic profiles, compound 14 demonstrated robust efficacy in preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma. Taken together, current studies indicate that 14 deserves further investigation as a potential lead RORγt agonist for cancer immunotherapy.
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Affiliation(s)
- Lixue Lu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yafei Huang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Meiqi Song
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Nannan Sun
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Li Xia
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Mingcheng Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Meiling Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Ruomeng Qiu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Ji-An Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yunpeng Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Haojie Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Huimin Guo
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yan Li
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Di Zhu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yonghui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
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14
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Zhu H, Chen J, Wen Z, Li J, Yu Q, Liao W, Luo X. The role of circadian clock genes in colorectal carcinoma: Novel insights into regulatory mechanism and implications in clinical therapy. Life Sci 2023; 333:122145. [PMID: 37797685 DOI: 10.1016/j.lfs.2023.122145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/23/2023] [Accepted: 10/02/2023] [Indexed: 10/07/2023]
Abstract
Colorectal cancer (CRC) is a lethal malignancy with limited treatment strategies. Accumulating evidence indicates that CRC tumorigenesis, progression and metastasis are intimately associated with circadian clock, an inherent 24-h cycle oscillation of biochemical, physiological functions in almost every eukaryote. In the present review, we summarize the altered expression level of circadian genes in CRC and the prognosis associated with gene abundance switch. We illustrate the function and potential mechanisms of circadian genes in CRC pathogenesis and progression. Moreover, circadian based-therapeutic strategies including chronotherapy, therapeutics targeting potential circadian components, and melatonin treatment in CRC are also highlighted.
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Affiliation(s)
- Haodong Zhu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Jiawei Chen
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Zeqin Wen
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China
| | - Jinfei Li
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Qinyang Yu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Weihua Liao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China; Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan 410078, PR China; Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China; Molecular Imaging Research Center of Central South University, Changsha, Hunan 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410078, PR China.
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15
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Pastwińska J, Karwaciak I, Karaś K, Bachorz RA, Ratajewski M. RORγT agonists as immune modulators in anticancer therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:189021. [PMID: 37951483 DOI: 10.1016/j.bbcan.2023.189021] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/26/2023] [Accepted: 11/04/2023] [Indexed: 11/14/2023]
Abstract
RORγT is a transcription factor that directs the development of Th17 lymphocytes and other IL-17-expressing cells (e.g., Tc17 and ILC3 cells). These cells are involved in the body's defense against pathogenic bacteria and fungi, but they also participate in maintaining the proinflammatory environment in some autoimmune diseases and play a role in the immune system's response to cancer. Similar to other members of the nuclear receptor superfamily, the activity of RORγT is regulated by low-molecular-weight ligands. Therefore, extensive efforts have been dedicated to identifying inverse agonists that diminish the activity of this receptor and subsequently inhibit the development of autoimmune diseases. Unfortunately, in the pursuit of an ideal inverse agonist, the development of agonists has been overlooked. It is important to remember that these types of compounds, by stimulating lymphocytes expressing RORγT (Th17 and Tc17), can enhance the immune system's response to tumors. In this review, we present recent advancements in the biology of RORγT agonists and their potential application in anticancer therapy.
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Affiliation(s)
- Joanna Pastwińska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Iwona Karwaciak
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Kaja Karaś
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Rafał A Bachorz
- Laboratory of Molecular Modeling, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Marcin Ratajewski
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
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16
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Liu Y, Wang Z, Hao H, Wang Y, Hua L. Insight into immune checkpoint inhibitor therapy for colorectal cancer from the perspective of circadian clocks. Immunology 2023; 170:13-27. [PMID: 37114514 DOI: 10.1111/imm.13647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 04/02/2023] [Indexed: 04/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumours and the third most common cause of cancer deaths worldwide, with high morbidity and mortality. Circadian clocks are widespread in humans and temporally regulate physiologic functions to maintain homeostasis. Recent studies showed that circadian components were strong regulators of the tumour immune microenvironment (TIME) and the immunogenicity of CRC cells. Therefore, insight into immunotherapy from the perspective of circadian clocks can be promising. Although immunotherapy, especially immune checkpoint inhibitor (ICI) treatment, has been a milestone in cancer treatment, greater accuracy is still needed for selecting patients who will respond positively to immunotherapy with minimal side effects. In addition, there were few reviews focusing on the role of the circadian components in the TIME and the immunogenicity of CRC cells. Therefore, this review highlights the crosstalk between the TIME in CRC and the immunogenicity of CRC cells based on the circadian clocks. With the goal to achieve the possibility that patients with CRC can benefit most from the ICI treatment, we provide potential evidence and a novel idea for building a predictive framework combined with circadian factors, searching for enhancers of ICIs targeting circadian components and clinically implementing the timing of ICI treatment for patients with CRC.
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Affiliation(s)
- Yanhong Liu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zeqin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Hankun Hao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yaping Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Luchun Hua
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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17
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Mei L, Xu L, Wu S, Wang Y, Xu C, Wang L, Zhang X, Yu C, Jiang H, Zhang X, Bai F, Xie C. Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of RORγ antagonists. Eur J Med Chem 2023; 257:115472. [PMID: 37236000 DOI: 10.1016/j.ejmech.2023.115472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/26/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023]
Abstract
Betulinic acid (BA) is a natural pentacyclic triterpenoid that has a wide range of biological and pharmacological effects. Here, computational methods such as pharmacophore screening and reverse docking were used to predict the potential target for BA. Retinoic acid receptor-related orphan receptor gamma (RORγ) was confirmed as its target by several molecular assays as well as crystal complex structure determination. RORγ has been the focus of metabolic regulation, but its potential role in cancer treatment has only recently come to the fore. In this study, rationale optimization of BA was performed and several new derivatives were generated. Among them, the compound 22 showed stronger binding affinity with RORγ (KD = 180 nM), good anti-proliferative activity against cancer cell lines, and potent anti-tumor efficacy with a TGI value of 71.6% (at a dose of 15 mg/kg) in the HPAF-II pancreatic cancer xenograft model. Further RNA-seq analysis and cellular validation experiments supported that RORγ antagonism was closely related to the antitumor activity of BA and 22, resulting in suppression of the RAS/MAPK and AKT/mTORC1 pathway and inducing caspase-dependent apoptosis in pancreatic cancer cells. RORγ was highly expressed in cancer cells and tissues and positively correlated with the poor prognosis of cancer patients. These results suggest that BA derivatives are potential RORγ antagonists worthy of further exploration.
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Affiliation(s)
- Lianghe Mei
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Lansong Xu
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Sanan Wu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Yafang Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China
| | - Chao Xu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Lin Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Xingyu Zhang
- China Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China
| | - Chengcheng Yu
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Hualiang Jiang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Xianglei Zhang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
| | - Fang Bai
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China.
| | - Chengying Xie
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
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18
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Sun N, Yu M, Jiang Z, Yang F, Lu L, Xia Y, Zhao Y, Huang Y, Chen S, Chen S, Luo C, Wang Y, Xie Q. Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity. Eur J Med Chem 2023; 251:115213. [PMID: 36905917 DOI: 10.1016/j.ejmech.2023.115213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/26/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
Based on two previously discovered carbazole carboxamide retinoic acid receptor-related orphan receptor-γt (RORγt) agonists 6 and 7 (t1/2 = 8.7 min and 16.4 min in mouse liver microsome, respectively), new carbazole carboxamides were designed and synthesized according to the molecular mechanism of action (MOA) and metabolic site analysis with the aim of identifying novel RORγt agonists with optimal pharmacological and metabolic profiles. By modifying the "agonist lock" touching substitutions on carbazole ring, introducing heteroatoms into different parts of the molecule and attaching a side chain to the sulfonyl benzyl moiety, several potent RORγt agonists were identified with greatly improved metabolic stability. Best overall properties were achieved in compound (R)-10f with high agonistic activities in RORγt dual FRET (EC50 = 15.6 nM) and Gal4 reporter gene (EC50 = 141 nM) assays and greatly improved metabolic stability (t1/2 > 145 min) in mouse liver microsome. Besides, the binding modes of (R)-10f and (S)-10f in RORγt ligand binding domain (LBD) were also studied. Altogether, the optimization of carbazole carboxamides led to the discovery of (R)-10f as a potential small molecule therapeutics for cancer immunotherapy.
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Affiliation(s)
- Nannan Sun
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China; Fudan Zhangjiang Institute, Shanghai, 201203, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Mingcheng Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Zhengyuan Jiang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Feng Yang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Lixue Lu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Yuehan Xia
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Yunpeng Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Yafei Huang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Song Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China
| | - Shijie Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Cheng Luo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Yonghui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China.
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China; Fudan Zhangjiang Institute, Shanghai, 201203, China.
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19
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Wang Y, Guo H, He F. Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets. Cancer Metastasis Rev 2023; 42:297-322. [PMID: 36513953 DOI: 10.1007/s10555-022-10072-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/25/2022] [Indexed: 12/15/2022]
Abstract
The circadian clock is a timekeeping system for numerous biological rhythms that contribute to the regulation of numerous homeostatic processes in humans. Disruption of circadian rhythms influences physiology and behavior and is associated with adverse health outcomes, especially cancer. However, the underlying molecular mechanisms of circadian disruption-associated cancer initiation and development remain unclear. It is essential to construct good circadian disruption models to uncover and validate the detailed molecular clock framework of circadian disruption in cancer development and progression. Mouse models are the most widely used in circadian studies due to their relatively small size, fast reproduction cycle, easy genome manipulation, and economic practicality. Here, we reviewed the current mouse models of circadian disruption, including suprachiasmatic nuclei destruction, genetic engineering, light disruption, sleep deprivation, and other lifestyle factors in our understanding of the crosstalk between circadian rhythms and oncogenic signaling, as well as the molecular mechanisms of circadian disruption that promotes cancer growth. We focused on the discoveries made with the nocturnal mouse, diurnal human being, and cell culture and provided several circadian rhythm-based cancer therapeutic strategies.
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Affiliation(s)
- Yu Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Haidong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Feng He
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Xia L, Tian E, Yu M, Liu C, Shen L, Huang Y, Wu Z, Tian J, Yu K, Wang Y, Xie Q, Zhu D. RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers. J Exp Clin Cancer Res 2022; 41:155. [PMID: 35459193 PMCID: PMC9034499 DOI: 10.1186/s13046-022-02289-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/15/2022] [Indexed: 01/01/2023] Open
Abstract
Abstract
Background
The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive.
Methods
The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression.
Results
We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration.
Conclusion
Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers.
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21
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Wu Y, Yang Z, Cheng K, Bi H, Chen J. Small molecule-based immunomodulators for cancer therapy. Acta Pharm Sin B 2022; 12:4287-4308. [PMID: 36562003 PMCID: PMC9764074 DOI: 10.1016/j.apsb.2022.11.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to pharmacodynamics (e.g., specificity and efficacy). However, they have limitations in terms of pharmacokinetics including long half-lives, poor tissue/tumor penetration, and little/no oral bioavailability. In addition, therapeutic antibodies are immunogenic, thus may cause unwanted adverse effects. Therefore, researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy, as small molecules may overcome the above disadvantages associated with antibodies. Further, small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment, and may be combined to elicit synergistic effects. Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy. In this review, we describe the current progress in small molecule-based immunomodulators (inhibitors/agonists/degraders) for cancer therapy, including those targeting PD-1/PD-L1, chemokine receptors, stimulator of interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.
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Affiliation(s)
| | | | - Kui Cheng
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jianjun Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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22
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Long M, Mims AS, Li Z. Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement. Immunol Invest 2022; 51:2176-2214. [PMID: 36259611 DOI: 10.1080/08820139.2022.2131569] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
T-cell bispecific antibodies (T-BsAbs) are a new class of cancer immunotherapy drugs that can simultaneously bind to tumor-associated antigens on target cells and to the CD3 subunit of the T-cell receptor (TCR) on T cells. In the last decade, numerous T-BsAbs have been developed for the treatment of both hematological malignancies and solid tumors. Among them, blinatumomab has been successfully used to treat CD19 positive malignancies and has been approved by the FDA as standard care for acute lymphoblastic leukemia (ALL). However, in many clinical scenarios, the efficacy of T-BsAbs remains unsatisfactory. To further improve T-BsAb therapy, it will be crucial to better understand the factors affecting treatment efficacy and the nature of the T-BsAb-induced immune response. Herein, we first review the studies on the potential mechanisms by which T-BsAbs activate T-cells and how they elicit efficient target killing despite suboptimal costimulatory support. We focus on analyzing reports from clinical trials and preclinical studies, and summarize the factors that have been identified to impact the efficacy of T-BsAbs. Lastly, we review current and propose new approaches to improve the clinical efficacy of T-BsAbs.
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Affiliation(s)
- Meixiao Long
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.,Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Alice S Mims
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.,Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
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23
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Amiama-Roig A, Verdugo-Sivianes EM, Carnero A, Blanco JR. Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy. Cancers (Basel) 2022; 14:5071. [PMID: 36291855 PMCID: PMC9599830 DOI: 10.3390/cancers14205071] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/19/2022] [Accepted: 09/25/2022] [Indexed: 08/19/2023] Open
Abstract
Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right functioning of the body. An individual's circadian system is altered during aging, and this is related to numerous age-associated pathologies and other alterations that could contribute to the development of cancer. Nowadays, there is an increasing interest in understanding how circadian rhythms could be used in the treatment of cancer. Chronotherapy aims to understand the impact that biological rhythms have on the response to a therapy to optimize its action, maximize health benefits and minimize possible adverse effects. Clinical trials so far have confirmed that optimal timing of treatment with chemo or immunotherapies could decrease drug toxicity and increase efficacy. Instead, chronoradiotherapy seems to minimize treatment-related symptoms rather than tumor progression or patient survival. In addition, potential therapeutic targets within the molecular clock have also been identified. Therefore, results of the application of chronotherapy in cancer therapy until now are challenging, feasible, and could be applied to clinical practice to improve cancer treatment without additional costs. However, different limitations and variables such as age, sex, or chronotypes, among others, should be overcome before chronotherapy can really be put into clinical practice.
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Grants
- RTI2018-097455-B-I00 Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I+D+I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE):
- RED2018-102723-T Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I+D+I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE):
- CB16/12/00275 Centro de Investigación Biomédica en Red de Cáncer
- PI-0397-2017 Consejería de Salud y Familias
- P18-RT-2501 Consejería de Transformacion Economica, Industria, Conocimiento, y Universidades of the Junta de Andalucía
- No. CTEICU/PAIDI 2020 Consejería de Transformacion Economica, Industria, Conocimiento, y Universidades of the Junta de Andalucía
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Affiliation(s)
- Ana Amiama-Roig
- Hospital Universitario San Pedro, 26006 Logroño, Spain
- Centro de Investigación Biomédica de La Rioja (CIBIR), 26006 Logroño, Spain
| | - Eva M. Verdugo-Sivianes
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Seville, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Seville, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José-Ramón Blanco
- Hospital Universitario San Pedro, 26006 Logroño, Spain
- Centro de Investigación Biomédica de La Rioja (CIBIR), 26006 Logroño, Spain
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24
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Halada S, Casado-Medrano V, Baran JA, Lee J, Chinmay P, Bauer AJ, Franco AT. Hormonal Crosstalk Between Thyroid and Breast Cancer. Endocrinology 2022; 163:6588704. [PMID: 35587175 PMCID: PMC9653009 DOI: 10.1210/endocr/bqac075] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/09/2022]
Abstract
Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations-adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes-promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal therapies for breast and thyroid cancer. Future research efforts should acknowledge and further explore the hormonal crosstalk of these tissues in an effort to further understand the prevalence of thyroid and breast cancer in women and to identify potential therapeutic options.
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Affiliation(s)
- Stephen Halada
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Victoria Casado-Medrano
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Julia A Baran
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Joshua Lee
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Poojita Chinmay
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Andrew J Bauer
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aime T Franco
- Correspondence: Aime T. Franco, Ph.D., Pediatric Thyroid Center Translational Laboratory, The University of Pennsylvania and Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
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25
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Yang N, Yang Y, Huang Z, Chen HW. Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer. Cancers (Basel) 2022; 14:3110. [PMID: 35804882 PMCID: PMC9265016 DOI: 10.3390/cancers14133110] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 01/26/2023] Open
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) features high intratumoral cholesterol levels, due to aberrant regulation of cholesterol homeostasis. However, the underlying mechanisms are still poorly understood. The retinoid acid receptor-related orphan receptor gamma (RORγ), an attractive therapeutic target for cancer and autoimmune diseases, is strongly implicated in prostate cancer progression. We demonstrate in this study that in mCRPC cells and tumors, RORγ plays a crucial role in deregulation of cholesterol homeostasis. First, we found that RORγ activates the expression of key cholesterol biosynthesis proteins, including HMGCS1, HMGCR, and SQLE. Interestingly, we also found that RORγ inhibition induces cholesterol efflux gene program including ABCA1, ABCG1 and ApoA1. Our further studies revealed that liver X receptors (LXRα and LXRβ), the master regulators of cholesterol efflux pathway, mediate the function of RORγ in repression of cholesterol efflux. Finally, we demonstrated that RORγ antagonist in combination with statins has synergistic effect in killing mCRPC cells through blocking statin-induced feedback induction of cholesterol biosynthesis program and that the combination treatment also elicits stronger anti-tumor effects than either alone. Altogether, our work revealed that in mCRPC, RORγ contributes to aberrant cholesterol homeostasis by induction of cholesterol biosynthesis program and suppression of cholesterol efflux genes. Our findings support a therapeutic strategy of targeting RORγ alone or in combination with statin for effective treatment of mCRPC.
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Affiliation(s)
- Nianxin Yang
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; (N.Y.); (Y.Y.); (Z.H.)
| | - Yatian Yang
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; (N.Y.); (Y.Y.); (Z.H.)
| | - Zenghong Huang
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; (N.Y.); (Y.Y.); (Z.H.)
| | - Hong-Wu Chen
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; (N.Y.); (Y.Y.); (Z.H.)
- National Cancer Institute Designated Comprehensive Cancer Center, University of California, Davis, Sacramento, CA 95817, USA
- Veterans Affairs Northern California Health Care System, Mather, CA 95655, USA
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26
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Neves AR, Albuquerque T, Quintela T, Costa D. Circadian rhythm and disease: Relationship, new insights, and future perspectives. J Cell Physiol 2022; 237:3239-3256. [PMID: 35696609 DOI: 10.1002/jcp.30815] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 05/25/2022] [Accepted: 06/02/2022] [Indexed: 02/01/2023]
Abstract
The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.
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Affiliation(s)
- Ana R Neves
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Covilhã, Portugal
| | - Tânia Albuquerque
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Covilhã, Portugal
| | - Telma Quintela
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Covilhã, Portugal.,Unidade de Investigação para o Desenvolvimento do Interior (UDI-IPG), Instituto Politécnico da Guarda, Guarda, Portugal
| | - Diana Costa
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Covilhã, Portugal
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27
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ABCB1 restricts brain accumulation of the novel RORγ agonist cintirorgon, while OATP1A/1B and CYP3A limit its oral availability. Eur J Pharm Biopharm 2022; 177:135-146. [DOI: 10.1016/j.ejpb.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/29/2022] [Accepted: 06/16/2022] [Indexed: 11/21/2022]
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28
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Zhou L, Zhang Z, Nice E, Huang C, Zhang W, Tang Y. Circadian rhythms and cancers: the intrinsic links and therapeutic potentials. J Hematol Oncol 2022; 15:21. [PMID: 35246220 PMCID: PMC8896306 DOI: 10.1186/s13045-022-01238-y] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The circadian rhythm is an evolutionarily conserved time-keeping system that comprises a wide variety of processes including sleep-wake cycles, eating-fasting cycles, and activity-rest cycles, coordinating the behavior and physiology of all organs for whole-body homeostasis. Acute disruption of circadian rhythm may lead to transient discomfort, whereas long-term irregular circadian rhythm will result in the dysfunction of the organism, therefore increasing the risks of numerous diseases especially cancers. Indeed, both epidemiological and experimental evidence has demonstrated the intrinsic link between dysregulated circadian rhythm and cancer. Accordingly, a rapidly increasing understanding of the molecular mechanisms of circadian rhythms is opening new options for cancer therapy, possibly by modulating the circadian clock. In this review, we first describe the general regulators of circadian rhythms and their functions on cancer. In addition, we provide insights into the mechanisms underlying how several types of disruption of the circadian rhythm (including sleep-wake, eating-fasting, and activity-rest) can drive cancer progression, which may expand our understanding of cancer development from the clock perspective. Moreover, we also summarize the potential applications of modulating circadian rhythms for cancer treatment, which may provide an optional therapeutic strategy for cancer patients.
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Affiliation(s)
- Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Edouard Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Wei Zhang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yong Tang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Acupuncture and Chronobiology Laboratory of Sichuan Province, Chengdu, 610075, China.
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29
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Passaro A, Brahmer J, Antonia S, Mok T, Peters S. Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies. J Clin Oncol 2022; 40:598-610. [PMID: 34985992 DOI: 10.1200/jco.21.01845] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.
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Affiliation(s)
- Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Julie Brahmer
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | | | - Tony Mok
- State Key Laboratory in Translational Oncology, Department of Clinical Oncology Chinese University of Hong Kong, Hong Kong, P.R. China
| | - Solange Peters
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
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30
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Gil J, Marques-Pamies M, Valassi E, García-Martínez A, Serra G, Hostalot C, Fajardo-Montañana C, Carrato C, Bernabeu I, Marazuela M, Rodríguez-Lloveras H, Cámara R, Salinas I, Lamas C, Biagetti B, Simó-Servat A, Webb SM, Picó A, Jordà M, Puig-Domingo M. Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response. Biomedicines 2022; 10:biomedicines10020460. [PMID: 35203668 PMCID: PMC8962441 DOI: 10.3390/biomedicines10020460] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 12/04/2022] Open
Abstract
Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making.
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Affiliation(s)
- Joan Gil
- Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), 08916 Barcelona, Spain; (J.G.); (H.R.-L.)
- Research Center for Pituitary Diseases, Department of Endocrinology/Medicine, Hospital Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; (E.V.); (S.M.W.)
| | - Montserrat Marques-Pamies
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain; (M.M.-P.); (I.S.)
| | - Elena Valassi
- Research Center for Pituitary Diseases, Department of Endocrinology/Medicine, Hospital Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; (E.V.); (S.M.W.)
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain; (M.M.-P.); (I.S.)
| | - Araceli García-Martínez
- Department of Endocrinology & Nutrition, Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain; (A.G.-M.); (A.P.)
- Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Guillermo Serra
- Department of Endocrinology, Son Espases University Hospital, 07120 Palma de Mallorca, Spain;
| | - Cristina Hostalot
- Department of Neurosurgery, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain;
| | | | - Cristina Carrato
- Department of Pathology, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain;
| | - Ignacio Bernabeu
- Endocrinology Division, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, 15706 Santiago de Compostela, Spain;
| | - Mónica Marazuela
- Department of Endocrinology, Hospital de la Princesa, Instituto Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain;
| | - Helena Rodríguez-Lloveras
- Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), 08916 Barcelona, Spain; (J.G.); (H.R.-L.)
| | - Rosa Cámara
- Endocrinology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain;
| | - Isabel Salinas
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain; (M.M.-P.); (I.S.)
| | - Cristina Lamas
- Department of Endocrinology and Nutrition, Hospital General Universitario de Albacete, 02006 Albacete, Spain;
| | - Betina Biagetti
- Department of Endocrinology, University Hospital Vall d’Hebron, 08035 Barcelona, Spain;
| | - Andreu Simó-Servat
- Department of Endocrinology, Hospital Universitari Mutua Terrassa, 08221 Terrassa, Spain;
| | - Susan M. Webb
- Research Center for Pituitary Diseases, Department of Endocrinology/Medicine, Hospital Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; (E.V.); (S.M.W.)
| | - Antonio Picó
- Department of Endocrinology & Nutrition, Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain; (A.G.-M.); (A.P.)
- Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Clinical Medicine, Miguel Hernandez University, 03202 Elche, Spain
| | - Mireia Jordà
- Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), 08916 Barcelona, Spain; (J.G.); (H.R.-L.)
- Correspondence: (M.J.); (M.P.-D.); Tel.: +34-93-033-05-19 (ext. 6260) (M.J.); +34-934-978-655 (M.P.-D.)
| | - Manel Puig-Domingo
- Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), 08916 Barcelona, Spain; (J.G.); (H.R.-L.)
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, 08916 Barcelona, Spain; (M.M.-P.); (I.S.)
- Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona, 08913 Barcelona, Spain
- Correspondence: (M.J.); (M.P.-D.); Tel.: +34-93-033-05-19 (ext. 6260) (M.J.); +34-934-978-655 (M.P.-D.)
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31
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Heydari P, Li W, Schinkel AH, Beijnen JH, Sparidans RW. Development and validation of an LC-MS/MS assay for the quantification of cintirorgon (LYC-55716) in mouse plasma and tissue homogenates. J Pharm Biomed Anal 2022; 207:114421. [PMID: 34710729 DOI: 10.1016/j.jpba.2021.114421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 10/20/2022]
Abstract
Cintirorgon (LYC-55716) is a promising first-in-class antitumor agent as a RORγ agonist in the treatment against various types of cancer. To support preclinical mouse studies, a bioanalytical method was developed and successfully applied for quantification of cintirorgon in mouse plasma and tissue homogenates using LC-MS/MS. The method was fully validated in mouse plasma and partial validation was performed in eight different homogenates originating from brain, kidney, liver, lung, small intestine, small intestine content, spleen, and testis. Sample preparation was performed using 96-well plates for fast and efficient analysis. Protein precipitation was done by addition of 20 µL acetonitrile containing monensin as internal standard to 10 µL sample. Chromatographic separation was achieved on a Polaris 3 C18-A column using gradient elution with 0.2% (v/v) formic acid and 0.2% (v/v) ammonium hydroxide in water (A) and methanol (B) as eluents. The total run time was 3 min. Detection was carried out with a triple quadrupole mass spectrometer with electrospray ionization operated in the positive ion-mode. Quantification could be accomplished within a linear validated concentration range of 5-4,000 ng/mL (10-4,000 ng/mL in brain homogenates) with an intra- and inter-day precision between 4.6-14.7% and 5.1-15.6% (including the LLOQ), respectively, and accuracies between 89.1%-111.2%. The method was successfully applied to a preclinical study with cintirorgon in mice.
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Affiliation(s)
- Paniz Heydari
- Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands; The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
| | - Wenlong Li
- Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands; The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands
| | - Alfred H Schinkel
- The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands
| | - Jos H Beijnen
- Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands; The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; The Netherlands Cancer Institute, Department of Clinical Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Rolf W Sparidans
- Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands
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32
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Chen JA, Ma H, Liu Z, Tian J, Lu S, Fang W, Ze S, Lu W, Xie Q, Huang J, Wang Y. Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease. J Med Chem 2021; 65:592-615. [PMID: 34957834 DOI: 10.1021/acs.jmedchem.1c01746] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 μM for RORγt and of 0.297 μM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.
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Affiliation(s)
- Ji-An Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Hui Ma
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Zehui Liu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Jinlong Tian
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Sisi Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Wenqing Fang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Shuyin Ze
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.,Fudan Zhangjiang Institute, 666 Zhangheng Road, Shanghai 201203, China
| | - Jin Huang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Yonghui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
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DeRatt LG, Wang CY, Kuduk SD. Tandem Amination/Oxetane Ring Opening toward Benzomorpholines. J Org Chem 2021; 86:17482-17486. [PMID: 34807596 DOI: 10.1021/acs.joc.1c02166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Herein, a tandem approach that allows rapid access to the benzomorpholine scaffold is reported. This operationally simple method allows for valuable heterocycles to be isolated in moderate to high yields. The overall transformation consists of an initial C-N coupling, demonstrated using traditional Ullmann or Buchwald-Hartwig conditions, followed by an in situ oxetane ring opening. A range of functionality is tolerated on the aryl ring, and the cyclization exposes a pendant hydroxymethyl substituent, providing opportunities for further functionalization.
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Affiliation(s)
- Lindsey G DeRatt
- Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States
| | - Chao-Yuan Wang
- Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States
| | - Scott D Kuduk
- Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States
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Saenz SA, Local A, Carr T, Shakya A, Koul S, Hu H, Chourb L, Stedman J, Malley J, D’Agostino LA, Shanmugasundaram V, Malona J, Schwartz CE, Beebe L, Clements M, Rajaraman G, Cho J, Jiang L, Dubrovskiy A, Kreilein M, Shimanovich R, Hamann LG, Escoubet L, Ellis JM. Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. PLoS One 2021; 16:e0248034. [PMID: 34752458 PMCID: PMC8577775 DOI: 10.1371/journal.pone.0248034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 10/25/2021] [Indexed: 11/19/2022] Open
Abstract
Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.
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Affiliation(s)
- Steven A. Saenz
- Immunology, Cardiovascular & Fibrosis, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
- * E-mail: (SAS); (JME)
| | - Andrea Local
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, California, United States of America
| | - Tiffany Carr
- Immunology, Cardiovascular & Fibrosis, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Arvind Shakya
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, California, United States of America
| | - Shivsmriti Koul
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, California, United States of America
| | - Haiqing Hu
- Preclinical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Lisa Chourb
- Preclinical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Justin Stedman
- Preclinical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Jenna Malley
- Nonclinical Development, Celgene Corporation, Cambridge, Massachusetts, United States of America
| | - Laura Akullian D’Agostino
- Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | | | - John Malona
- Drug Substance Development, Bristol Myers Squibb, Summit, New Jersey, United States of America
| | - C. Eric Schwartz
- Drug Substance Development, Bristol Myers Squibb, Summit, New Jersey, United States of America
| | - Lisa Beebe
- Preclinical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Meghan Clements
- Nonclinical Development, Celgene Corporation, Cambridge, Massachusetts, United States of America
| | - Ganesh Rajaraman
- Nonclinical Development, Celgene Corporation, Cambridge, Massachusetts, United States of America
| | - John Cho
- Immunology & Inflammation, Celgene Corporation, Cambridge, Massachusetts, United States of America
| | - Lan Jiang
- Immunology, Cardiovascular & Fibrosis, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Alex Dubrovskiy
- Immunology, Cardiovascular & Fibrosis, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Matt Kreilein
- Drug Substance Development, Bristol Myers Squibb, Summit, New Jersey, United States of America
| | - Roman Shimanovich
- Preclinical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Lawrence G. Hamann
- Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
| | - Laure Escoubet
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, California, United States of America
| | - J. Michael Ellis
- Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, Massachusetts, United States of America
- * E-mail: (SAS); (JME)
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Li Z, Liu T, He X, Bai C. The evolution paths of some reprehensive scaffolds of RORγt modulators, a perspective from medicinal chemistry. Eur J Med Chem 2021; 228:113962. [PMID: 34776280 DOI: 10.1016/j.ejmech.2021.113962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/19/2021] [Accepted: 10/27/2021] [Indexed: 11/29/2022]
Abstract
The ligand binding domain (LBD) of retinoid-related orphan nuclear receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to cure autoimmune diseases via modulating the IL-17 and IL-22 production by Th17 cells. Diverse chemical scaffolds of these small molecules have been discovered by multiple groups with methods such as high throughput screening (HTS) and virtual screening. These different scaffolds are further developed by medicinal chemists to afford lead compounds the best of which enter clinical trials. In this review, we summarize these chemical scaffolds and their evolution paths according to the groups in which they have been discovered or studied. We combine the data of the chemistry, biological assays and structural biology of each chemical scaffold, in order to afford insight to develop new RORγt modulators with higher potency, less toxicity and elucidated working mechanism.
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Affiliation(s)
- Zhuohao Li
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Tao Liu
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Xixin He
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Chuan Bai
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
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Lu B, Liu D, Gui B, Gou J, Dong H, Hu Q, Feng J, Mao Y, Shen X, Wang S, Zhang C, Shen R, Yan Y, Chen L, Wang H, Li D, Zhang J, Zhang M, Zhang R, Bai C, He F, Tao W, Liu S. Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity. J Med Chem 2021; 64:14983-14996. [PMID: 34643383 DOI: 10.1021/acs.jmedchem.1c00828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure-activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound 17 that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the in vivo antitumor efficacy of an RORγ agonist.
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Affiliation(s)
- Biao Lu
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Dong Liu
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Bin Gui
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Jun Gou
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Huaide Dong
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Qiyue Hu
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Jun Feng
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Yuchang Mao
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Xiaodong Shen
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Shenglan Wang
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Caihua Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Ru Shen
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Yinfa Yan
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Lei Chen
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Huiyun Wang
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Di Li
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Jiayin Zhang
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Minsheng Zhang
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Rumin Zhang
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
| | - Chang Bai
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Feng He
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Weikang Tao
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China
| | - Suxing Liu
- Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States
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37
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Tian EM, Yu MC, Feng M, Lu LX, Liu CL, Shen LA, Wang YH, Xie Q, Zhu D. RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-β signaling in cancer. Pharmacol Res 2021; 172:105793. [PMID: 34339836 DOI: 10.1016/j.phrs.2021.105793] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 10/20/2022]
Abstract
To date, the overall response rate to checkpoint blockade remains unsatisfactory, partially due to the limited understanding of the tumor immune microenvironment. The retinoic acid-related orphan receptor γt (RORγt) is the key transcription factor of T helper cell 17 (Th17) cells and plays an essential role in tumor immunity. In this study, we used JG-1, a potent and selective small-molecule RORγt agonist to evaluate the therapeutic potential and mechanism of action of targeting RORγt in tumor immunity. JG-1 promotes Th17 cells differentiation and inhibition of regulatory T (Treg) cells differentiation. JG-1 demonstrates robust tumor growth inhibition in multiple syngeneic models and shows a synergic effect with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody. In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-β1 (TGF-β1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4.
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Affiliation(s)
- En-Ming Tian
- Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Ming-Cheng Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Mei Feng
- Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Li-Xue Lu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Cheng-Long Liu
- Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Li-An Shen
- Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yong-Hui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
| | - Di Zhu
- Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China; School of Basic Medical Sciences, Fudan Unvieristy, Shanghai 200032, China.
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Aicher TD, Van Huis CA, Hurd AR, Skalitzky DJ, Taylor CB, Beleh OM, Glick G, Toogood PL, Yang B, Zheng T, Huo C, Gao J, Qiao C, Tian X, Zhang J, Demock K, Hao LY, Lesch CA, Morgan RW, Moisan J, Wang Y, Scatina J, Paulos CM, Zou W, Carter LL, Hu X. Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer. J Med Chem 2021; 64:13410-13428. [PMID: 34499493 DOI: 10.1021/acs.jmedchem.1c00731] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.
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Affiliation(s)
- Thomas D Aicher
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Chad A Van Huis
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Alexander R Hurd
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Donald J Skalitzky
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Clarke B Taylor
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Omar M Beleh
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Gary Glick
- Chief Scientific Officer, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Peter L Toogood
- Department of Chemistry, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Bing Yang
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Tao Zheng
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Changxin Huo
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Jie Gao
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Chenxi Qiao
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Xiaolong Tian
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Junping Zhang
- Department of Chemistry, Pharmaron Beijing, Co. Ltd., Beijing 100176, P. R. China
| | - Kellie Demock
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Ling-Yang Hao
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Charles A Lesch
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Rodney W Morgan
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Jacques Moisan
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Yahong Wang
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - JoAnn Scatina
- Department of Preclinical Development, Lycera Corp., 620 Germantown Pike, Plymouth Meeting, Pennsylvania 19462, United States
| | - Chrystal M Paulos
- Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, MSC 509, Room 203, Charleston, South Carolina 29425, United States
| | - Weiping Zou
- School of Medicine, Department of Surgery, University of Michigan, 2101 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Laura L Carter
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
| | - Xiao Hu
- Department of Biology, Lycera Corp., 1350 Highland Drive, Suite A, Ann Arbor, Michigan 48108, United States
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Yu MC, Yang F, Ding XY, Sun NN, Jiang ZY, Huang YF, Yan YR, Zhu C, Xie Q, Chen ZF, Guo SQ, Jiang HL, Chen KX, Luo C, Luo XM, Chen SJ, Wang YH. Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with "short" and "long" inverse agonists. Acta Pharmacol Sin 2021; 42:1524-1534. [PMID: 33239687 PMCID: PMC8379218 DOI: 10.1038/s41401-020-00552-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of RORγt complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of RORγt. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.
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Affiliation(s)
- Ming-Cheng Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Feng Yang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiao-Yu Ding
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Nan-Nan Sun
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
- Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zheng-Yuan Jiang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Ya-Fei Huang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yu-Rong Yan
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Chen Zhu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
- Fudan Zhangjiang Institute, Shanghai, 201203, China
| | - Zhi-Feng Chen
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Si-Qi Guo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hua-Liang Jiang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China
| | - Kai-Xian Chen
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Cheng Luo
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China
| | - Xiao-Min Luo
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Shi-Jie Chen
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Yong-Hui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
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Ma X, Sun N, Li X, Fu W. Discovery of novel N-sulfonamide-tetrahydroisoquinolines as potent retinoic acid receptor-related orphan receptor γt agonists. Eur J Med Chem 2021; 222:113585. [PMID: 34118722 DOI: 10.1016/j.ejmech.2021.113585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022]
Abstract
Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small molecule immuno-oncology agents, including retinoic acid-related orphan receptor gamma t (RORγt), chemokine receptor, stimulator of interferon genes (Sting), indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR), etc. Among them, the retinoic acid receptor-related orphan receptor γt (RORγt) has gradually attracted more attention in these years. In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study. In this work, starting from compound 7, compound 28 was obtained after 4 rounds of compound design, synthesis and SAR studies, which had an EC50 of 0.021 ± 0.002 μM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC50 of 0.021 ± 0.002 μM in mouse Th17 cell differentiation assay. It indicated that compound 28 had excellent RORγt agonistic activity and was expected to be developed as a new type of small molecule drug for cancer immunotherapy. The molecular dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramolecular interaction to stabilize H12, which helped RORγt to form the protein-binding site and therefore made the receptor ready to recruit coactivator. When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt.
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Affiliation(s)
- Xiaojun Ma
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China
| | - Nannan Sun
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China
| | - Xinwei Li
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China
| | - Wei Fu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
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Pan X, Li B, Zhang G, Gong Y, Liu R, Chen B, Li Y. Identification of RORγ as a favorable biomarker for colon cancer. J Int Med Res 2021; 49:3000605211008338. [PMID: 33947261 PMCID: PMC8113924 DOI: 10.1177/03000605211008338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective To evaluate the expression of retinoid-related orphan receptor gamma (RORγ)
and its potential role in the prognosis of colon cancer. Methods The Cancer Genome Atlas and GSE117606 were used to evaluate to RORγ levels in
colon cancer, and real-time quantitative polymerase chain reaction was
applied for validation. UALCAN and MEXPRESS were used to analyze the
associations of RORγ expression with clinical parameters. The survival
analysis was conducted in GEPIA. Results RORγ expression was significantly lower in colon tumors than in adjacent
normal mucosa tissues. RORγ expression was significantly associated with
tumor stage, lymph node metastasis, and liver metastasis. The area under the
curve for diagnosis was 0.71. Decreased RORγ expression was positively
correlated with the incidence of lymphatic invasion, microsatellite
instability, the presence of residual tumor, venous invasion, and copy
number variation. Overall survival was longer in patients with higher RORγ
expression, especially those with microsatellite instability-high features.
Methylation analysis revealed that hypermethylation of the RORγ promoter was
associated with the colon cancer stage. Conclusions RORγ downregulation could be a potential biomarker for colon cancer,
especially for predicting prognosis. Decreased RORγ expression in colon
tumor may be associated with promoter hypermethylation.
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Affiliation(s)
- Xiaofei Pan
- Department of Colorectal and Anal Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Bao Li
- Department of Colorectal and Anal Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Gan Zhang
- Department of Colorectal and Anal Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Yuyong Gong
- Department of Colorectal and Anal Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Rui Liu
- Department of Burns and Orthopedic Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Benxin Chen
- Department of Minimally Invasive Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
| | - Yang Li
- Department of Colorectal and Anal Surgery, the Affiliated Hospital of West Anhui Health Vocational College, Lu'an, China
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Rasmussen LG, Verbeke CS, Sørensen MD, Pfeiffer P, Tan Q, Mortensen MB, Fristrup C, Detlefsen S. Gene expression profiling of morphologic subtypes of pancreatic ductal adenocarcinoma using surgical and EUS-FNB specimens. Pancreatology 2021; 21:530-543. [PMID: 33637450 DOI: 10.1016/j.pan.2021.01.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 12/21/2020] [Accepted: 01/31/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND/OBJECTIVES Various classifications of pancreatic ductal adenocarcinoma (PDAC) based on RNA profiling resulted in two main subtypes. Kalimuthu and coworkers proposed a morphology-based classification that concurred with these subtypes. Immune therapy approaches in PDAC were so far disappointing. Morphologic PDAC subtypes may differ regarding key immune-oncology pathways. We aimed to examine the reproducibility and prognostic value of Kalimuthu's morphologic classification, and to evaluate differences between subtypes regarding gene expression related to tumor biology and immune-oncology. METHODS PDAC specimens from 196 patients were included, 108 consecutive chemotherapy-naïve surgical specimens and 88 endoscopic ultrasound-guided fine needle biopsies (EUS-FNBs). The specimens were evaluated as per Kalimuthu by two pancreatic pathologists, resulting in Group A and Group B tumors. Digital mRNA expression profiling was performed, on the surgical specimens using the NanoString IO360 panel of 770 key tumor biology related and 30 custom-genes, and on the EUS-FNBs using a targeted panel of 123 genes. RESULTS Morphologic subtyping reached substantial interobserver agreement between the two pathologists. In the surgical and EUS-FNB cohorts, 44.4% and 38.6% were Group A tumors, which were associated with improved survival. Group A showed higher expression of immune-related genes and cytokine/chemokine/interleukin signaling and Group B of genes related to cancer cell proliferation and cell cycle regulation. Hierarchical clustering based on significant differences in gene expression levels between Groups A and B revealed clusters with prognostic value. CONCLUSIONS Morphologic subtyping according to Kalimuthu is reproducible and holds prognostic value, in surgical as well as EUS-FNB specimens. As upregulation of immune-related genes was found in Group A, future studies should evaluate the potential of immune therapy approaches with special emphasis on this subtype of PDAC.
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Affiliation(s)
- Lukas Gammelgaard Rasmussen
- Department of Pathology, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Caroline Sophie Verbeke
- Department of Pathology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Mia Dahl Sørensen
- Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Per Pfeiffer
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Qihua Tan
- Epidemiology and Biostatistics, Department of Public Health & Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Michael Bau Mortensen
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Surgery, Upper GI and HPB Section, Odense University Hospital, Odense, Denmark
| | - Claus Fristrup
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Surgery, Upper GI and HPB Section, Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
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Cash E, Sephton S, Woolley C, Elbehi AM, R I A, Ekine-Afolabi B, Kok VC. The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics. J Exp Clin Cancer Res 2021; 40:119. [PMID: 33794967 PMCID: PMC8017624 DOI: 10.1186/s13046-021-01919-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.
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Affiliation(s)
- Elizabeth Cash
- Department of Otolaryngology and Communicative Disorders, University of Louisville School of Medicine, James Graham Brown Cancer Center, 529 S Jackson Street, Louisville, KY, 40202, USA.
| | - Sandra Sephton
- Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, USA
| | - Cassandra Woolley
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Attia M Elbehi
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Anu R I
- Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Kerala, India
| | - Bene Ekine-Afolabi
- ZEAB Therapeutic Ltd, London, UK
- Department of Health, Sport & Bioscience, University of East London, Stratford, UK
| | - Victor C Kok
- Department of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University Taiwan, Taichung, Taiwan
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Ribeiro RFN, Cavadas C, Silva MMC. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discov Today 2021; 26:1620-1641. [PMID: 33781946 DOI: 10.1016/j.drudis.2021.03.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/20/2021] [Accepted: 03/16/2021] [Indexed: 12/29/2022]
Abstract
Disruption of circadian oscillations has a wide-ranging impact on health, with the potential to induce the development of clock-related diseases. Small-molecule modulators of the circadian clock (SMMCC) target core or noncore clock proteins, modulating physiological effects as a consequence of agonist, inverse agonist, or antagonist interference. These pharmacological modulators are usually identified using chemical screening of large libraries of active compounds. However, target-based screens, chemical optimization, and circadian crystallography have recently assisted in the identification of these compounds. In this review, we focus on established and novel SMMCCs targeting both core and noncore clock proteins, identifying their circadian targets, detailed circadian effects, and specific physiological effects. In addition, we discuss their therapeutic potential for the treatment of diverse clock-related disorders (such as metabolic-associated disorders, autoimmune diseases, mood disorders, and cancer) and as chronotherapeutics. Future perspectives are also considered, such as clinical trials, and potential safety hazards, including those in the absence of clinical trials.
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Affiliation(s)
- Rodrigo F N Ribeiro
- Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Centre for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Cláudia Cavadas
- Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Centre for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
| | - Maria Manuel C Silva
- Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Centre for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
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45
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Kang JH, Bluestone JA, Young A. Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines. Trends Immunol 2021; 42:293-311. [PMID: 33714688 DOI: 10.1016/j.it.2021.02.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/08/2021] [Accepted: 02/08/2021] [Indexed: 12/17/2022]
Abstract
Cancer immunotherapies can successfully activate immune responses towards certain tumors. However, this can also result in the development of treatment-induced immune-related adverse events (irAEs) in multiple tissues. Growing evidence suggests that cytokine production in response to these therapeutics potentiates the development of irAEs and may have predictive value as biomarkers for irAE occurrence. In addition, therapeutic agents that inhibit cytokine activity can limit the severity of irAEs, and their use is being tested in the clinical setting. This review provides an in-depth analysis of strategies to uncouple the cytokine response, that precipitates irAEs following cancer immunotherapies, from the benefit gained in promoting antitumor immunity.
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Affiliation(s)
- Jee Hye Kang
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Jeffrey A Bluestone
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA; Sonoma Biotherapeutics, South San Francisco, CA, USA
| | - Arabella Young
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
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Strategies to overcome resistance to immune checkpoint blockade in lung cancer. Lung Cancer 2021; 154:151-160. [PMID: 33684660 DOI: 10.1016/j.lungcan.2021.02.035] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/20/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
The adoption of Immune checkpoint inhibitors (ICIs) allowed the achievement of impressive long-term survival results in non-small cell lung cancer (NSCLC), but most patients develop resistance to ICI treatment over time. Resistance to ICIs is mediated by several complex mechanisms affecting, but not limited to, tumour cell-intrinsic alterations and the tumour microenvironment. The possibility of modulating the immune response by interfering with specific alternative immune receptors, pathways and mediators might provide additional strategies to delay or prevent the development of resistance. Therefore, a greater in-depth investigation and understanding of these mechanisms aims to identify novel classes of immune targets and subsequently to evaluate potential new strategies for overcoming resistance, which will be assessed in this review.
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47
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Astone M, Santoro MM. Time to fight: targeting the circadian clock molecular machinery in cancer therapy. Drug Discov Today 2021; 26:1164-1184. [PMID: 33549826 DOI: 10.1016/j.drudis.2021.01.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/23/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023]
Abstract
The circadian clock regulates a wide range of molecular pathways and biological processes. The expression of clock genes is often altered in cancer, fostering tumor initiation and progression. Inhibition and activation of core circadian clock genes, as well as treatments that restore circadian rhythmicity, have been successful in counteracting tumor growth in different experimental models. Here, we provide an up-to-date overview of studies that show the therapeutic effects of targeting the clock molecular machinery in cancer, both genetically and pharmacologically. We also highlight future areas for progress that offer a promising path towards innovative anticancer strategies. Substantial limitations in the current understanding of the complex interplay between the circadian clock and cancer in vivo need to be addressed in order to allow clock-targeting therapies in cancer.
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Affiliation(s)
- Matteo Astone
- Department of Biology, University of Padova, I-35131, Italy
| | - Massimo M Santoro
- Department of Biology, University of Padova, I-35131, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
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Ladurner A, Schwarz PF, Dirsch VM. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs). Nat Prod Rep 2021; 38:757-781. [PMID: 33118578 DOI: 10.1039/d0np00047g] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Covering: 1994 to 2020 Retinoic acid receptor-related orphan receptors (RORs) belong to a subfamily of the nuclear receptor superfamily and possess prominent roles in circadian rhythm, metabolism, inflammation, and cancer. They have been subject of research for over two decades and represent attractive but challenging drug targets. Natural products were among the first identified ligands of RORs and continue to be of interest to this day. This review focuses on ligands and indirect modulators of RORs from natural sources and explores their roles in a therapeutic context.
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Affiliation(s)
- Angela Ladurner
- Department of Pharmacognosy, University of Vienna, Vienna, Austria.
| | - Patrik F Schwarz
- Department of Pharmacognosy, University of Vienna, Vienna, Austria.
| | - Verena M Dirsch
- Department of Pharmacognosy, University of Vienna, Vienna, Austria.
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49
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Immune Therapy: What Can We Learn From Acquired Resistance? Lung Cancer 2021. [DOI: 10.1007/978-3-030-74028-3_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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50
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Kuen DS, Kim BS, Chung Y. IL-17-Producing Cells in Tumor Immunity: Friends or Foes? Immune Netw 2020; 20:e6. [PMID: 32158594 PMCID: PMC7049578 DOI: 10.4110/in.2020.20.e6] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/25/2020] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
IL-17 is produced by RAR-related orphan receptor gamma t (RORγt)-expressing cells including Th17 cells, subsets of γδT cells and innate lymphoid cells (ILCs). The biological significance of IL-17-producing cells is well-studied in contexts of inflammation, autoimmunity and host defense against infection. While most of available studies in tumor immunity mainly focused on the role of T-bet-expressing cells, including cytotoxic CD8+ T cells and NK cells, and their exhaustion status, the role of IL-17-producing cells remains poorly understood. While IL-17-producing T-cells were shown to be anti-tumorigenic in adoptive T-cell therapy settings, mice deficient in type 17 genes suggest a protumorigenic potential of IL-17-producing cells. This review discusses the features of IL-17-producing cells, of both lymphocytic and myeloid origins, as well as their suggested pro- and/or anti-tumorigenic functions in an organ-dependent context. Potential therapeutic approaches targeting these cells in the tumor microenvironment will also be discussed.
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Affiliation(s)
- Da-Sol Kuen
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.,BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Byung-Seok Kim
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.,BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
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