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Liao H, Zheng J, Lu J, Shen HL. NF-κB Signaling Pathway in Rheumatoid Arthritis: Mechanisms and Therapeutic Potential. Mol Neurobiol 2025; 62:6998-7021. [PMID: 39560902 DOI: 10.1007/s12035-024-04634-2] [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: 03/11/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.
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Affiliation(s)
- Haiyang Liao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Jianxiong Zheng
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Jinyue Lu
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Hai-Li Shen
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China.
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2
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Famurewa AC, Akhigbe RE, George MY, Adekunle YA, Oyedokun PA, Akhigbe TM, Fatokun AA. Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4747-4778. [PMID: 39636404 PMCID: PMC11985630 DOI: 10.1007/s00210-024-03623-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 11/08/2024] [Indexed: 12/07/2024]
Abstract
Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc-/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.
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Affiliation(s)
- Ademola C Famurewa
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University Ndufu-Alike, Ikwo, Nigeria.
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
| | - Roland E Akhigbe
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Nigeria
| | - Mina Y George
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Yemi A Adekunle
- Department of Pharmaceutical and Medicinal Chemistry, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Precious A Oyedokun
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Nigeria
| | - Tunmise M Akhigbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Nigeria
- Breeding and Genetics Unit, Department of Agronomy, Osun State University, Osogbo, Osun State, Nigeria
| | - Amos A Fatokun
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK
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Zhou K, Zhang S, Shang J, Lan X. Exploring immune gene expression and potential regulatory mechanisms in anaplastic thyroid carcinoma using a combination of single-cell and bulk RNA sequencing data. Comput Biol Chem 2025; 115:108311. [PMID: 39674047 DOI: 10.1016/j.compbiolchem.2024.108311] [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: 04/22/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/16/2024]
Abstract
Thyroid cancer includes papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). While PTC has an excellent prognosis, ATC has a dismal prognosis, necessitating the identification of novel targets in ATC to aid in ATC diagnosis and treatment. Therefore, we analyzed ATC single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data from the Gene Expression Omnibus (GEO), retrieved immune-related genes from the ImmPort database, and identified differentially expressed immune genes within single-cell subgroups. The AUCell package in R was used to calculate activity scores for single-cell subgroups and identify active cell populations. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on differentially expressed genes (DEGs) in active cell populations. Then, we integrated thyroid-cancer scRNA-seq and bulk RNA-seq data to identify overlapping DEGs. Relevant transcription factors (TFs) were retrieved from the TRRUST database. A protein-protein interaction (PPI) network for key TFs was created using the STRING database. Simultaneously, drugs associated with key TFs were obtained from DGIdb. ScRNA-seq cluster analysis showed that T/natural killer (NK) cells were more distributed in ATC and that thyrocytes cells were more distributed in PTC. We obtained 264 differential immune genes (DIGs) from the IMMPORT database and integrated scRNA-seq cluster analysis to identify the active cell T/NK cells and myeloid cells. Integrated bulk RNA-seq analysis obtained common immune genes (CIGs) such as TMSB4X, NFKB1, TNFRSF1B, and B2M. The nine CIG-related TFs (CEBPB, SPI1, NFKB1, RUNX1, NFE2L2, REL, CIITA, KLF6, and CEBPD) in myeloid cells and three TFs (NFKB1, FOXO1, and NR3C1) in T/NK cells were obtained from the TRRUST database. The key genes we identified represent potential targets for treating ATC.
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Affiliation(s)
- Kehui Zhou
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Department of Thyroid Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Shijia Zhang
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Department of Thyroid Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jinbiao Shang
- Department of Thyroid Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310022, China
| | - Xiabin Lan
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Department of Thyroid Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310022, China.
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Wang S, Xu D, Xiao L, Liu B, Yuan X. Radiation-induced lung injury: from mechanism to prognosis and drug therapy. Radiat Oncol 2025; 20:39. [PMID: 40082925 PMCID: PMC11907960 DOI: 10.1186/s13014-025-02617-8] [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: 11/14/2024] [Accepted: 02/28/2025] [Indexed: 03/16/2025] Open
Abstract
Radiation induced lung injury, known as the main complication of thoracic radiation, remains to be a major resistance to tumor treatment. Based on the recent studies on radiation-induced lung injury, this review collated the possible mechanisms at the level of target cells and key pathways, corresponding prognostic models including predictors, patient size, number of centers, radiotherapy technology, construction methods and accuracy, and pharmacotherapy including drugs, targets, therapeutic effects, impact on anti-tumor treatment and research types. The research priorities and limitations are summarized to provide a reference for the research and management of radiation-induced lung injury.
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Affiliation(s)
- Sheng Wang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, 210000, China
| | - Duo Xu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Lingyan Xiao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Deng RM, Huang G, Wang T, Zhou J. Regulated programmed cell death in sepsis associated acute lung injury: From pathogenesis to therapy. Int Immunopharmacol 2025; 148:114111. [PMID: 39832461 DOI: 10.1016/j.intimp.2025.114111] [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: 09/09/2024] [Revised: 11/28/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Sepsis associated acute lung injury (SALI) is a common complication in patients with severe sepsis and a disease with high morbidity and mortality in ICU patients. The main mechanism of SALI is pulmonary hypoperfusion due to hypotension and shock caused by sepsis, which leads to ischemic necrosis of alveolar endothelial cells and eventually lung failure. At present, SALI therapy mainly includes antibiotic therapy, fluid resuscitation, transfusion products and vasoactive drugs, but these strategies are not satisfactory. Therefore, focusing on the role of different cell death patterns in SALI may help in the search for effective treatments. Understanding the molecular mechanisms of SALI and identifying pathways that inhibit lung cell death are critical to developing effective drug therapies to prevent the progression of SALI. Cell death is controlled by programmed cell death (PCD) pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis and autophagy. There is growing evidence that PCD plays an important role in the pathogenesis of SALI, and inhibitors of various types of PCD represent a promising therapeutic strategy. Therefore, understanding the role and mechanism of PCD in SALI is conducive to our understanding of its pathological mechanism, and is of great significance for the treatment of SALI. In this article, we discuss recent advances in the role of PCD in SALI, show how different signaling pathways (such as NF-κB, PI3K/Akt, mTOR, and Nrf2) regulate PCD to regulate SALI development, and discuss the associations between various types of PCD. The aim is to explore the molecular mechanism behind SALI and to find new targets for SALI therapy.
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Affiliation(s)
- Rui-Ming Deng
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
| | - Guiming Huang
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China
| | - Tingting Wang
- Department of Anaesthesia, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, PR China
| | - Juan Zhou
- Department of Thyroid and Breast Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
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Wang Z, Liu Y, Asemi Z. Quercetin and microRNA Interplay in Apoptosis Regulation: A New Therapeutic Strategy for Cancer? Curr Med Chem 2025; 32:939-957. [PMID: 38018191 DOI: 10.2174/0109298673259466231031050437] [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: 04/25/2023] [Revised: 07/06/2023] [Accepted: 10/09/2023] [Indexed: 11/30/2023]
Abstract
Cancer is known as a global problem for the health and economy. Following cancer onset, apoptosis is the primary mechanism countering the tumor cells' growth. Most anticancer agents initiate apoptosis to remove tumor cells. Phytochemicals have appeared as a beneficial treatment option according to their less adverse effects. In recent decades, quercetin has been highlighted due to its high pharmacological benefits, and various literature has suggested it as a potential anti-proliferative agent against different kinds of cancers. The microRNAs (miRNAs) play key roles in cancer treatment, progression, and apoptosis. This review reviewed the effect of quercetin on miRNAs contributing to the induction or inhibition of apoptosis in cancers.
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Affiliation(s)
- Zicheng Wang
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China
- Department of Pharmacology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Yanqing Liu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China
- Department of Pharmacology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Zatollah Asemi
- Department of Nutrition, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
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Liu D, Zhu K, Guo T, Xiao Y, Wang M, Guan Y, Li J, Chang D, Yu X. Chrysophanol: A promising natural compound in cancer therapy - Mechanistic insights and future perspectives. Pharmacol Res 2024; 210:107502. [PMID: 39521026 DOI: 10.1016/j.phrs.2024.107502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/26/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Cancer continues to be a leading cause of death worldwide, highlighting the urgent need for the development of new therapeutic strategies. Chrysophanol, a naturally occurring anthraquinone compound, has demonstrated significant potential in cancer treatment due to its diverse biological activities. This review delves into the mechanisms through which chrysophanol exerts its anti-cancer effects, including the induction of cell cycle arrest, promotion of apoptosis, regulation of autophagy, and initiation of necrosis across various cancer cell lines. Additionally, the review discusses chrysophanol's impact on inhibiting cancer cell invasion and metastasis and its role in modulating chemotherapy sensitivity. Despite the promising therapeutic potential of chrysophanol, challenges such as poor water solubility, low bioavailability, and safety concerns remain. Comprehensive clinical trials are essential to validate its efficacy and safety. This review emphasizes chrysophanol as a promising candidate for cancer therapy and underscores the necessity for further research to fully harness its therapeutic potential.
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Affiliation(s)
- Dehong Liu
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Kun Zhu
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Tao Guo
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yao Xiao
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Meijing Wang
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yanxin Guan
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Junjun Li
- Chengdu Fifth People's Hospital, The Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Degui Chang
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, China.
| | - Xujun Yu
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, China.
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8
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Galal SM, El Kiki SM, Elgazzar EM. The Potential Therapeutic Approach of Ursodeoxycholic Acid as a Potent Activator of ACE-2 on Cerebral Disorders Induced by γ-irradiation in Rats. Cell Biochem Funct 2024; 42:e70024. [PMID: 39660593 DOI: 10.1002/cbf.70024] [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: 06/12/2024] [Revised: 11/05/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024]
Abstract
The present investigation assesses ursodeoxycholic acid's efficacy (UDCA) as an ACE2 activator against gamma irradiation through activating the renin-angiotensin system's (RAS) beneficial axis, ACE2/Ang-(1-7)/Mas1 via its profitable influence on inflammation, oxidative stress, and neuronal damage caused by irradiation (IRR). Four groups of rats were treated as follows: control group, group receiving UDCA (100 mg/kg/day) for 14 days by gavage, group irradiated at 6 Gy, and group receiving UDCA post-irradiation for 14 days. The results revealed that gamma-irradiation (6 Gy) caused a substantial drop in the cerebral ACE2/Ang-(1-7)/Mas1 axis and remarkably increased the expression of cerebral inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6) and interleukin-1β (IL-1β) combined with significant elevation in cyclooxygenase-II (COX-II), (NADPH) oxidases (NOX4), lipooxygenase (LOX) activities and nitric oxide (NO) content. Moreover, it greatly enhanced the reduction in N-methyl-d-aspartate (NMDA) level, while dramatically increasing gamma-aminobutyric acid (GABA) level and neuronal nitric oxide synthases (nNOS) enzyme activity in cerebral tissue homogenate. Irradiated rats' brain sections underwent histological investigation using hematoxylin and eosin staining, which revealed cellular damage and a pathological appearance. The administration of UDCA inverts these unusual alterations. In conclusion, UDCA treatment efficiently normalizes the above-mentioned pathological abnormalities and avoids the development of IRR-associated neurological dysfunction by upregulating the beneficial axis of RAS in the brain. Hence, ursodeoxycholic acid presents a novel option for patient care during radiotherapy.
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Affiliation(s)
- Shereen Mohamed Galal
- Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Shereen Mohamed El Kiki
- Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Eman Mahmoud Elgazzar
- Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
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Golla U, Patel S, Shah N, Talamo S, Bhalodia R, Claxton D, Dovat S, Sharma A. From Deworming to Cancer Therapy: Benzimidazoles in Hematological Malignancies. Cancers (Basel) 2024; 16:3454. [PMID: 39456548 PMCID: PMC11506385 DOI: 10.3390/cancers16203454] [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: 08/16/2024] [Revised: 09/30/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers.
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Affiliation(s)
- Upendarrao Golla
- Division of Hematology and Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; (U.G.); (D.C.)
- Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Satyam Patel
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
| | - Nyah Shah
- Department of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
| | - Stella Talamo
- Department of Medicine, Liberty University College of Osteopathic Medicine, Lynchburg, VA 24502, USA;
| | - Riya Bhalodia
- Division of Hematology and Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; (R.B.); (S.D.)
| | - David Claxton
- Division of Hematology and Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; (U.G.); (D.C.)
| | - Sinisa Dovat
- Division of Hematology and Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; (R.B.); (S.D.)
| | - Arati Sharma
- Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
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10
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Ma Z, Liu X, Zhang M, Wu Z, Zhang X, Li S, An J, Luo Z. Research Progress on the Role of Cartilage Endplate in Intervertebral Disc Degeneration. Cell Biochem Funct 2024; 42:e4118. [PMID: 39267363 DOI: 10.1002/cbf.4118] [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: 07/19/2024] [Revised: 08/24/2024] [Accepted: 08/26/2024] [Indexed: 09/17/2024]
Abstract
Low back pain significantly impacts individuals' quality of life, with intervertebral disc degeneration (IDD) being a primary contributor to this condition. Currently, IDD treatment primarily focuses on symptom management and does not achieve a definitive cure. The cartilage endplate (CEP), a crucial nutrient-supplying tissue of the intervertebral disc, plays a pivotal role in disc degeneration. This review examines the mechanisms underlying CEP degeneration, summarizing recent advancements in understanding the structure and function of CEP, the involvement of various signaling pathways, and the roles of cartilage endplate stem cells (CESCs) and exosomes (Exos) in this process. The aim of this review is to provide a comprehensive reference for future research on CEP. Despite progress in understanding the role of CEP in IDD, the mechanisms underlying CEP degeneration remain incompletely elucidated. Future research poses significant challenges, necessitating further investigations to elucidate the complexities of CEP.
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Affiliation(s)
- Zhong Ma
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xin Liu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Mingtao Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zuolong Wu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xianxu Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Shicheng Li
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Jiangdong An
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zhiqiang Luo
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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11
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Mohammed SM, Al-Saedi HFS, Mohammed AQ, Amir AA, Radi UK, Sattar R, Ahmad I, Ramadan MF, Alshahrani MY, Balasim HM, Alawadi A. Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches. Cell Biochem Biophys 2024; 82:1845-1870. [PMID: 38955925 DOI: 10.1007/s12013-024-01384-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 07/04/2024]
Abstract
Pulmonary toxicity is a serious side effect of some specific anticancer drugs. Bleomycin is a well-known anticancer drug that triggers severe reactions in the lungs. It is an approved drug that may be prescribed for the treatment of testicular cancers, Hodgkin's and non-Hodgkin's lymphomas, ovarian cancer, head and neck cancers, and cervical cancer. A large number of experimental studies and clinical findings show that bleomycin can concentrate in lung tissue, leading to massive oxidative stress, alveolar epithelial cell death, the proliferation of fibroblasts, and finally the infiltration of immune cells. Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis. Both fibrosis and pneumonitis are serious concerns for patients who receive bleomycin and may lead to death. Therefore, the management of lung toxicity following cancer therapy with bleomycin is a critical issue. This review explains the cellular and molecular mechanisms of pulmonary injury following treatment with bleomycin. Furthermore, we review therapeutic targets and possible promising strategies for ameliorating bleomycin-induced lung injury.
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Affiliation(s)
- Shaimaa M Mohammed
- Department of Pharmacy, Al- Mustaqbal University College, 51001, Hilla, Babylon, Iraq
| | | | | | - Ahmed Ali Amir
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Usama Kadem Radi
- College of Pharmacy, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ruaa Sattar
- Al-Hadi University College, Baghdad, 10011, Iraq
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
| | - Halah Majeed Balasim
- Department of Medical Laboratory Technologies, Al Rafidain University College, Bagdad, Iraq
| | - Ahmed Alawadi
- College of technical engineering, the Islamic University, Najaf, Iraq
- College of technical engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of technical engineering, the Islamic University of Babylon, Hilla, Iraq
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12
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Cao X, Xiang J, Zhang Q, Liu J, Zhou D, Xu Y, Xu P, Chen B, Bai H. Multidimensional role of adapalene in regulating cell death in multiple myeloma. Front Pharmacol 2024; 15:1415224. [PMID: 39175546 PMCID: PMC11338798 DOI: 10.3389/fphar.2024.1415224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/19/2024] [Indexed: 08/24/2024] Open
Abstract
Aims Multiple myeloma (MM) remains a challenging condition to cure, with persistent drug resistance negating the benefits of treatment advancements. The unraveling complexities in programmed cell death (PCD), inclusive of apoptosis, autophagy, and ferroptosis, have highlighted novel therapeutic avenues. Our study focuses on deciphering how adapalene (ADA), a small molecule compound, accelerates the demise of MM cells via targeting their compensatory survival mechanisms. Methods To assess the impact of ADA on MM, we employed flow cytometry and trypan blue exclusion assays to determine cell viabilities across MM cell lines and primary patient samples post-treatment. To delineate ADA's therapeutic targets and mechanisms, we conducted RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations. We further designed pre-clinical trials emphasizing MM, exploring the efficacy of ADA as a standalone and in combination with bortezomib (BTZ). Results ADA elicited a dose-responsive induction of MM cell death. Building upon ADA's anti-MM capabilities as a single agent, we proposed that ADA-BTZ co-treatment might amplify this lethality. Indeed, ADA and BTZ together greatly potentiated MM cell death. ADA proved beneficial in restoring BTZ susceptibility in BTZ-resistant relapsed or refractory MM (RRMM) patient cells. Molecular simulations highlighted ADA's high affinity (-9.17 kcal/mol) for CD138, with MM-GBSA revealing a binding free energy of -27.39 kcal/mol. Detailed interaction analyses indicated hydrogen-bonding of ADA with CD138 at the Asp35 and Gln34 residues. Additionally, ADA emerged as a versatile instigator of both ferroptosis and apoptosis in MM cells. Furthermore, ADA disrupted activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway triggered by BTZ, fostering cell death in BTZ-resistant MM subsets. Conclusion ADA demonstrates a comprehensive capability to orchestrate MM cell death, exerting pronounced anti-MM activity while disrupting NF-κB-related drug resistance. ADA sensitization of MM cells to BTZ unravels its potential as a novel therapeutic drug for MM management.
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Affiliation(s)
- Xinya Cao
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jie Xiang
- Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou, China
| | - Qi Zhang
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinwen Liu
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dongming Zhou
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yong Xu
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Peipei Xu
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bing Chen
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hua Bai
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Zhao P, Li H, Sun B, Wang C, Lv G, Chen C, Ying L, He X, Jin D, Bu W. Carbon Free Radical (R⋅) Inactivates NF-κB for Radical Capping Therapy. Angew Chem Int Ed Engl 2024; 63:e202405913. [PMID: 38683647 DOI: 10.1002/anie.202405913] [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: 03/27/2024] [Revised: 04/19/2024] [Accepted: 04/29/2024] [Indexed: 05/01/2024]
Abstract
Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon-centered free radicals (R⋅) can inactivate NF-κB transcription by capping the active sites in both NF-κB and DNA. We construct a type of thermosensitive R⋅ initiator loaded amphiphilic nano-micelles to facilitate intracellular delivery of R⋅. At a temperature of 43 °C, the generated R⋅ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF-κB through radical chain reaction. As a result, both NF-κB nuclear translocation and NF-κB-DNA binding are suppressed, leading to a remarkable NF-κB inhibition of up to 94.1 %. We have further applied R⋅ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF-κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat-sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.
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Affiliation(s)
- Peiran Zhao
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Huiyan Li
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Bingxia Sun
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, P. R. China
| | - Chaochao Wang
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, 200072, P. R. China
| | - Guanglei Lv
- Center for Biotechnology and Biomedical Engineering, Yiwu Research Institute of Fudan University, Yiwu, 322000, P. R. China
| | - Chao Chen
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center and department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Leilei Ying
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center and department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xinhong He
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center and department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Dayong Jin
- Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, New South Wales, 2007, Australia
| | - Wenbo Bu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
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Ding Y, Chen Q. Recent advances on signaling pathways and their inhibitors in spinal cord injury. Biomed Pharmacother 2024; 176:116938. [PMID: 38878684 DOI: 10.1016/j.biopha.2024.116938] [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: 04/12/2024] [Revised: 05/27/2024] [Accepted: 06/10/2024] [Indexed: 06/20/2024] Open
Abstract
Spinal cord injury (SCI) is a serious and disabling central nervous system injury. Its complex pathological mechanism can lead to sensory and motor dysfunction. It has been reported that signaling pathway plays a key role in the pathological process and neuronal recovery mechanism of SCI. Such as PI3K/Akt, MAPK, NF-κB, and Wnt/β-catenin signaling pathways. According to reports, various stimuli and cytokines activate these signaling pathways related to SCI pathology, thereby participating in the regulation of pathological processes such as inflammation response, cell apoptosis, oxidative stress, and glial scar formation after injury. Activation or inhibition of relevant pathways can delay inflammatory response, reduce neuronal apoptosis, prevent glial scar formation, improve the microenvironment after SCI, and promote neural function recovery. Based on the role of signaling pathways in SCI, they may be potential targets for the treatment of SCI. Therefore, understanding the signaling pathway and its inhibitors may be beneficial to the development of SCI therapeutic targets and new drugs. This paper mainly summarizes the pathophysiological process of SCI, the signaling pathways involved in SCI pathogenesis, and the potential role of specific inhibitors/activators in its treatment. In addition, this review also discusses the deficiencies and defects of signaling pathways in SCI research. It is hoped that this study can provide reference for future research on signaling pathways in the pathogenesis of SCI and provide theoretical basis for SCI biotherapy.
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Affiliation(s)
- Yi Ding
- Department of Spine Surgery, Ganzhou People's Hospital,16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University),16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China
| | - Qin Chen
- Department of Spine Surgery, Ganzhou People's Hospital,16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University),16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
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15
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He W, Li ZQ, Gu HY, Pan QL, Lin FX. Targeted Therapy of Spinal Cord Injury: Inhibition of Apoptosis Is a Promising Therapeutic Strategy. Mol Neurobiol 2024; 61:4222-4239. [PMID: 38066400 DOI: 10.1007/s12035-023-03814-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/16/2023] [Indexed: 07/11/2024]
Abstract
Spinal cord injury (SCI) is a serious disabling central nervous system injury that can lead to motor, sensory, and autonomic dysfunction below the injury level. SCI can be divided into primary injury and secondary injury according to pathological process. Primary injury is mostly irreversible, while secondary injury is a dynamic regulatory process. Apoptosis is an important pathological event of secondary injury and has a significant effect on the recovery of nerve function after SCI. Nerve cell death can further aggravate the microenvironment of the injured site, leading to neurological dysfunction and thus affect the clinical outcome of patients. Therefore, apoptosis plays a crucial role in the pathological progression of secondary SCI, while inhibiting apoptosis may be a promising therapeutic strategy for SCI. This review will summarize and explore the factors that lead to cell death after SCI, the influence of cross talk between signaling pathways and pathways involved in apoptosis and discuss the influence of apoptosis on SCI, and the therapeutic significance of targeting apoptosis on SCI. This review helps us to understand the role of apoptosis in secondary SCI and provides a theoretical basis for the treatment of SCI based on apoptosis.
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Affiliation(s)
- Wei He
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Zhi-Qiang Li
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Hou-Yun Gu
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Qi-Lin Pan
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Fei-Xiang Lin
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China.
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China.
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Wang Y, Deng X, Xie J, Lu T, Qian R, Guo Z, Zeng X, Liao J, Ding Z, Zhou M, Niu X. The COP9 signalosome stabilized MALT1 promotes Non-Small Cell Lung Cancer progression through activation of NF-κB pathway. Cell Biol Toxicol 2024; 40:45. [PMID: 38864940 PMCID: PMC11169058 DOI: 10.1007/s10565-024-09888-z] [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: 09/30/2023] [Accepted: 06/03/2024] [Indexed: 06/13/2024]
Abstract
MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.
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Affiliation(s)
- Yinghui Wang
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
- Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, China
| | - Xuyi Deng
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jing Xie
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Tianhao Lu
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Rui Qian
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhi Guo
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xin Zeng
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jing Liao
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhenhua Ding
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Xinli Niu
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, NMPA Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China.
- Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, China.
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Yang H, Zhao Y, Ren B, Wu Y, Qiu Z, Cheng Y, Qiu B. Poria acid inhibit the growth and metastasis of renal cell carcinoma by inhibiting the PI3K/akt/NF-κb signaling pathway. Heliyon 2024; 10:e31106. [PMID: 38779018 PMCID: PMC11109894 DOI: 10.1016/j.heliyon.2024.e31106] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Background Poria acid (PAC) is a triterpene compound found in Poria cocos, a traditional Chinese medicine (TCM). The current study aims to explore the therapeutic effects and potential mechanisms of PAC on the migration and proliferation of human renal cell carcinoma (RCC) cells as well as tumor growth in animal model. Methods Cell viability and proliferative capacity of normal renal cells and RCC cells were investigated by MTT assay. In addition, 786-O cells were divided into four groups and treated with different concentrations of PAC (0, 20, 40, and 60 μM) for 48 h. Cell scratch test and cell invasion assay were performed to evaluate the effects of PAC on the invasion and migration of RCC cells, respectively. The effects of PAC on apoptosis of RCC cells and expression levels of PI3K/Akt/NF-kB signaling pathway-related biomarkers were investigated using TUNEL staining and Western blotting methods, respectively. Effects of PAC on the inhibitory activity of RCC tumor in mice were evaluated in a 786-O CDX model. Results The study found that PAC inhibited the viability of RCC cells in a dose-dependent manner, as demonstrated by in vitro cell assays (p < 0.05). However, PAC showed no significant inhibitory effect on normal renal cells (p > 0.05). PAC also significantly inhibited the migration and invasion of RCC via EMT/MMP signaling pathways (p < 0.05). Immunofluorescence and immunoblotting results showed that PAC induced the apoptosis of RCC, which was accompanied by changes in the expression levels of apoptosis-related proteins (p < 0.05). Moreover, PAC significantly downregulated the PI3K/Akt/NF-kB signaling pathway in a concentration-dependent manner (p < 0.05). The effect of PAC on RCC apoptosis was dramatically reversed by 740Y-P (PI3K agonist) (p < 0.05) but significantly enhanced in the presence of LY294002 (PI3K inhibitor) (p < 0.05). The results of in vivo experiment also demonstrated that the antitumor activity of PAC was achieved by affecting the PI3K/Akt/NF-kB signaling pathway. Conclusions PAC can effectively suppress the proliferation, invasion and migration of RCC cells, and exhibit anti-tumor effects in RCC model by inhibiting the PI3K/Akt/NF-kB signaling pathway.
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Affiliation(s)
- Haotian Yang
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
| | - Yue Zhao
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
| | - Bingnan Ren
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
| | - Yin Wu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
| | - Zhihong Qiu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
| | - Yan Cheng
- Department of Medical Oncology, Hebei General Hospital, Shijiazhuang 050051, China
| | - Bo Qiu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
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Tang H, Zhou H, Zhang L, Tang T, Li N. Molecular mechanism of MLCK1 inducing 5-Fu resistance in colorectal cancer cells through activation of TNFR2/NF-κB pathway. Discov Oncol 2024; 15:159. [PMID: 38735014 PMCID: PMC11089027 DOI: 10.1007/s12672-024-01019-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 05/07/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND AND AIMS Chemotherapy resistance in colorectal cancer have been faced with significant challenges in recent years. Particular interest is directed to tumor microenvironment function. Recent work has, identified a small molecule named Divertin that prevents myosin light chain kinase 1(MLCK1) recruitment to the perijunctional actomyosin ring(PAMR), restores barrier function after tumor necrosis factor(TNF)-induced barrier loss and prevents disease progression in experimental inflammatory bowel disease. Studies have shown that MLCK is a potential target for affecting intestinal barrier function, as well as for tumor therapy. However, the relative contributions of MLCK expression and chemotherapy resistance in colorectal cancers have not been defined. METHODS Statistical analysis of MYLK gene expression differences in colorectal cancer patients and normal population and prognosis results from The Cancer Genome Atlas(TCGA) data. Cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. Determine the role of MLCK1 in inducing 5-Fluorouracil(5-Fu) resistance in colorectal cancer cells was detected by overexpression of MLCK1 and knock-down expression of MLCK1. RESULTS MLCK1 is expressed at different levels in different colorectal cancer cells, high MLCK1 expressing cell lines are less sensitive to 5-Fu, and low MLCK1 expressing cell lines are more sensitive to 5-Fu. MLCK1 high expression enhances resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway. CONCLUSIONS MLCK1 high expression can enhance resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway, which will provide a new method for the treatment of colorectal cancer patients who are resistant to 5-Fu chemotherapy.
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Affiliation(s)
- Huifen Tang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Hui Zhou
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Liang Zhang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Tingting Tang
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China
| | - Ning Li
- Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, 126# Wenzhou Road, Hangzhou, 310015, Zhejiang, People's Republic of China.
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Wei JY, Ma LX, Liu WT, Dong LH, Hou X, Bao XY, Hou W. Mechanisms and protective measures for radiation-induced brachial plexus nerve injury. Brain Res Bull 2024; 210:110924. [PMID: 38460911 DOI: 10.1016/j.brainresbull.2024.110924] [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: 10/07/2023] [Revised: 02/06/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]
Abstract
Radiation therapy is a common treatment modality for patients with malignant tumors of the head and neck, chest and axilla. However, radiotherapy inevitably causes damage to normal tissues at the irradiated site, among which damage to the brachial plexus nerve(BP) is a serious adverse effect in patients receiving radiation therapy in the scapular or axillary regions, with clinical manifestations including abnormal sensation, neuropathic pain, and dyskinesia, etc. These adverse effects seriously reduce the living quality of patients and pose obstacles to their prognosis. Therefore, it is important to elucidate the mechanism of radiation induced brachial plexus injury (RIBP) which remains unclear. Current studies have shown that the pathways of radiation-induced BP injury can be divided into two categories: direct injury and indirect injury, and the indirect injury is closely related to the inflammatory response, microvascular damage, cytokine production and other factors causing radiation-induced fibrosis. In this review, we summarize the underlying mechanisms of RIBP occurrence and possible effective methods to prevent and treat RIBP.
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Affiliation(s)
- Jia Ying Wei
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Li Xin Ma
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Wen Tong Liu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Li Hua Dong
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Xue Hou
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Xue Ying Bao
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Wei Hou
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China.
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20
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Zou JY, Chen QL, Luo XC, Damdinjav D, Abdelmohsen UR, Li HY, Battulga T, Chen HB, Wang YQ, Zhang JY. Natural products reverse cancer multidrug resistance. Front Pharmacol 2024; 15:1348076. [PMID: 38572428 PMCID: PMC10988293 DOI: 10.3389/fphar.2024.1348076] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/19/2024] [Indexed: 04/05/2024] Open
Abstract
Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.
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Affiliation(s)
- Jia-Yu Zou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qi-Lei Chen
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Xiao-Ci Luo
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Davaadagva Damdinjav
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Usama Ramadan Abdelmohsen
- Deraya Center for Scientific Research, Deraya University, New Minia, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Hong-Yan Li
- Ministry of Education Engineering Research Center of Tibetan Medicine Detection Technology, Xizang Minzu University, Xianyang, China
| | - Tungalag Battulga
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Hu-Biao Chen
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Yu-Qing Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- The Affiliated TCM Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jian-Ye Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, China
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21
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Yang Y, Chen Y, Tang H, Zhang Z, Zhou X, Xu W. DTTZ suppresses ferroptosis and reverses mitochondrial dysfunction in normal tissues affected by chemotherapy. Biomed Pharmacother 2024; 172:116227. [PMID: 38335570 DOI: 10.1016/j.biopha.2024.116227] [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: 11/10/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Conventional antineoplastic therapies cause severe normal tissue damage and existing cytoprotectants with acute toxicities or potential tumor protection limit their clinical application. We evaluated the selective cytoprotection of 2,2-dimethylthiazolidine hydrochloride in this study, which could protect normal tissue toxicity without interfering antineoplastic therapies. By using diverse cell lines and A549 xenograft model, we discovered a synthetic aminothiol 2,2-dimethylthiazolidine hydrochloride selectively diminished normal cellular ferroptosis via SystemXc-/Glutathione Peroxidase 4 pathway upon antineoplastic therapies without interfering the anticancer efficacy. We revealed the malignant and non-malignant tissues presenting different energy metabolism patterns. And cisplatin induces disparate replicative stress, contributing to the distinguishable cytoprotection of 2,2-dimethylthiazolidine in normal and tumor cells. The compound pre-application could mitigate cisplatin-induced normal cellular mitochondrial oxidative phosphorylation (OXPHOS) dysfunction. Pharmacologic ablation of mitochondria reversed 2,2-dimethylthiazolidine chemoprotection against cisplatin in the normal cell line. Combined, these results provide a potential therapeutic adjuvant to selectively diminish normal tissue damages retaining antineoplastic efficacy.
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Affiliation(s)
- Yuwei Yang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Yuanfang Chen
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Haikang Tang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Ziqi Zhang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Xiaoliang Zhou
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
| | - Wenqing Xu
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
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22
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Wu J, Ji H, Li T, Guo H, Xu H, Zhu J, Tian J, Gao M, Wang X, Zhang A. Targeting the prostate tumor microenvironment by plant-derived natural products. Cell Signal 2024; 115:111011. [PMID: 38104704 DOI: 10.1016/j.cellsig.2023.111011] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 10/31/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
Prostate cancer is among the most common malignancies for men, with limited therapy options for last stages of the tumor. There are some different options for treatment and control of prostate tumor growth. However, targeting some specific molecules and cells within tumors has been attracted interests in recent years. The tumor microenvironment (TME) has an important role in the initiation of various malignancies, which can also expand the progression of tumor and facilitate invasion of malignant cells. By regulating immune responses and distinct changes in the metabolism of cells in the tumor, TME has substantial effects in the resistance of cancer cells to therapy. TME in various solid cancers like prostate cancer includes various cells, including cancer cells, supportive stromal cells, immunosuppressive cells, and anticancer inflammatory cells. Natural products including herbal-derived agents and also other natural compounds have been well studied for their anti-tumor potentials. These compounds may modulate various signaling pathways involved in TME, such as immune responses, the metabolism of cells, epigenetics, angiogenesis, and extracellular matrix (ECM). This paper provides a review of the current knowledge of prostate TME and complex interactions in this environment. Additionally, the potential use of natural products and also nanoparticles loaded with natural products as therapeutic adjuvants on different cells and therapeutic targets within prostate TME will be discussed.
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Affiliation(s)
- Jiacheng Wu
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Hao Ji
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Tiantian Li
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Haifeng Guo
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - HaiFei Xu
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Jinfeng Zhu
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Jiale Tian
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Mingde Gao
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China
| | - Xiaolin Wang
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China.
| | - Aihua Zhang
- The operating room of Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, 226361, China.
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23
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Xiang Y, Chen Q, Nan Y, Liu M, Xiao Z, Yang Y, Zhang J, Ying X, Long X, Wang S, Sun J, Huang Q, Ai K. Nitric Oxide‐Based Nanomedicines for Conquering TME Fortress: Say “NO” to Insufficient Tumor Treatment. ADVANCED FUNCTIONAL MATERIALS 2024; 34. [DOI: 10.1002/adfm.202312092] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Indexed: 01/02/2025]
Abstract
AbstractAlmost all cancer treatments are significantly limited by the strong tumor microenvironment (TME) fortress formed by abnormal vasculature, dense extracellular matrix (ECM), multidrug resistance (MDR) system, and immune “cold” environment. In the huge efforts of dismantling the TME fortress, nitric oxide (NO)‐based nanomedicines are increasingly occupying a central position and have already been identified as super “strong polygonal warriors” to dismantle TME fortress for efficient cancer treatment, benefiting from NO's unique physicochemical properties and extremely fascinating biological effects. However, there is a paucity of systematic review to elaborate on the progress and fundamental mechanism of NO‐based nanomedicines in oncology from this aspect. Herein, the key characteristics of TME fortress and the potential of NO in reprogramming TME are delineated and highlighted. The evolution of NO donors and the advantages of NO‐based nanomedicines are discussed subsequently. Moreover, the latest progress of NO‐based nanomedicines for solid tumors is comprehensively reviewed, including normalizing tumor vasculature, overcoming ECM barrier, reversing MDR, and reactivating the immunosuppression TME. Lastly, the prospects, limitations, and future directions on NO‐based nanomedicines for TME manipulation are discussed to provide new insights into the construction of more applicable anticancer nanomedicines.
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Affiliation(s)
- Yuting Xiang
- Department of Pharmacy Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
| | - Qiaohui Chen
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Yayun Nan
- Geriatric Medical Center People's Hospital of Ningxia Hui Autonomous Region Yinchuan Ningxia 750002 P. R. China
| | - Min Liu
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Zuoxiu Xiao
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Yuqi Yang
- Department of Pharmacy Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
| | - Jinping Zhang
- Department of Pharmacy Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
| | - Xiaohong Ying
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Xingyu Long
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Shuya Wang
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
| | - Jian Sun
- College of Pharmacy Xinjiang Medical University Urumqi 830017 P. R. China
| | - Qiong Huang
- Department of Pharmacy Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 P. R. China
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences Central South University Changsha Hunan 410078 P. R. China
- Hunan Provincial Key Laboratory of Cardiovascular Research Xiangya School of Pharmaceutical Sciences Central South University Changsha 410078 P. R. China
- Key Laboratory of Aging‐related Bone and Joint Diseases Prevention and Treatment Ministry of Education Xiangya Hospital Central South University Changsha 410078 P. R. China
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24
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Prades-Sagarra E, Laarakker F, Dissy J, Lieuwes NG, Biemans R, Dubail M, Fouillade C, Yaromina A, Dubois LJ. Caffeic Acid Phenethyl Ester (CAPE), a natural polyphenol to increase the therapeutic window for lung adenocarcinomas. Radiother Oncol 2024; 190:110021. [PMID: 38000688 DOI: 10.1016/j.radonc.2023.110021] [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: 06/13/2023] [Revised: 10/16/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023]
Abstract
BACKGROUND AND PURPOSE Lung cancers are highly resistant to radiotherapy, necessitating the use of high doses, which leads to radiation toxicities such as radiation pneumonitis and fibrosis. Caffeic Acid Phenethyl Ester (CAPE) has been suggested to have anti-proliferative and pro-apoptotic effects in tumour cells, while radioprotective anti-inflammatory and anti-oxidant effects in the normal tissue. We investigated the radiosensitizing and radioprotective effects of CAPE in lung cancer cell lines and normal tissue in vitro and ex vivo, respectively. MATERIALS AND METHODS The cytotoxic and radiosensitizing effects of CAPE in lung cancer were investigated using viability and clonogenic survival assays. The radioprotective effects of CAPE were assessed in vitro and ex vivo using precision cut lung slices (PCLS). Potential underlying molecular mechanisms of CAPE focusing on cell cycle, cell metabolism, mitochondrial function and pro-inflammatory markers were investigated. RESULTS Treatment with CAPE decreased cell viability in a dose-dependent manner (IC50 57.6 ± 16.6 μM). Clonogenic survival assays showed significant radiosensitization by CAPE in lung adenocarcinoma lines (p < 0.05), while no differences were found in non-adenocarcinoma lines (p ≥ 0.13). Cell cycle analysis showed an increased S-phase (p < 0.05) after incubation with CAPE in the majority of cell lines. Metabolic profiling showed that CAPE shifted cellular respiration towards glycolysis (p < 0.01), together with mitochondrial membrane depolarization (p < 0.01). CAPE induced a decrease in NF-κB activity in adenocarcinomas and decreased pro-inflammatory gene expression in PCLS. CONCLUSION The combination of CAPE and radiotherapy may be a potentially effective approach to increase the therapeutic window in lung cancer patients.
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Affiliation(s)
- E Prades-Sagarra
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - F Laarakker
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - J Dissy
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - N G Lieuwes
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - R Biemans
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - M Dubail
- Institut Curie, Inserm U1021-CNRS UMR 3347, University Paris-Saclay, PSL University, Centre Universitaire, 91405 Orsay Cedex, France
| | - C Fouillade
- Institut Curie, Inserm U1021-CNRS UMR 3347, University Paris-Saclay, PSL University, Centre Universitaire, 91405 Orsay Cedex, France
| | - A Yaromina
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - L J Dubois
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands.
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25
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Hu Y, Yu H, Lai Y, Liu J, Tan Y, Lei W, Zhang J, Zhou X, Cao Y, Tang Y, Liu D, Zhang J. Longitudinal trajectory of amplitude of low-frequency fluctuation changes in breast cancer patients during neoadjuvant chemotherapy-A preliminary prospective study. Brain Res Bull 2024; 206:110845. [PMID: 38101650 DOI: 10.1016/j.brainresbull.2023.110845] [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: 09/20/2023] [Revised: 11/15/2023] [Accepted: 12/12/2023] [Indexed: 12/17/2023]
Abstract
There is growing evidence that the amplitude of low-frequency fluctuation (ALFF) changes in breast cancer patients after chemotherapy. However, longitudinal changes in ALFF during chemotherapy are unclear. To assess the trajectory of ALFF changes during chemotherapy, 36 breast cancer patients underwent both resting-state functional magnetic resonance imaging and neuropsychological testing at three time points, including before neoadjuvant chemotherapy (NAC) (time point 0, TP0), after one cycle of NAC (before the second cycle of NAC, TP1), and upon completion of NAC (pre-operation, TP2). Healthy controls (HC) received the same assessments at matching time points. We compared the longitudinal changes of ALFF in the NAC and two HC groups. In the NAC group, compared with TP0, ALFF values in the right orbital part of the inferior frontal gyrus, left medial orbital part of the superior frontal gyrus, right insula, left medial part of the superior frontal gyrus, and right middle frontal gyrus declined significantly at TP1 and TP2. Compared with TP1, there were no significant changes in ALFF values at TP2. In the two HC groups, there were no significant changes in ALFF at corresponding intervals. We concluded that for breast cancer patients receiving NAC, ALFF values declined significantly in some brain regions after one cycle of NAC and then remained stable until the completion of NAC, and most of the brain regions with ALFF changes were located in the frontal lobe.
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Affiliation(s)
- Yixin Hu
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Hong Yu
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yong Lai
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Jiang Liu
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yong Tan
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Weiwei Lei
- Department of Intensive Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Jing Zhang
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Xiaoyu Zhou
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Ying Cao
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yu Tang
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Daihong Liu
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China.
| | - Jiuquan Zhang
- Department of Radiology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China.
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26
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Samandari-Bahraseman MR, Ismaili A, Esmaeili-Mahani S, Ebrahimie E, Loit E. Bunium persicum Seeds Extract in Combination with Vincristine Mediates Apoptosis in MCF-7 Cells through Regulation of Involved Genes and Proteins Expression. Anticancer Agents Med Chem 2024; 24:213-223. [PMID: 38038013 DOI: 10.2174/0118715206277444231124051035] [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: 08/21/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 12/02/2023]
Abstract
BACKGROUND Bunium persicum seeds, a member of the Apiaceae family, have historically been consumed as part of the Iranian diet. OBJECTIVE While many of this herb's biological properties have been fully investigated, there is currently no reliable information about its anticancer/cytotoxic properties. METHODS Herein, we first determined the major bioactive compounds of B. persicum seed extract (BPSE) via GC-Mass analysis. We evaluated the cytotoxicity of the extract alone as well as in combination with vincristine (VCR), a commonly used chemotherapy drug, using MTT assays on two breast cancer cell lines, MCF-7 and MDA-MB-231, as well as a normal breast cancer cell line, MCF-10A. Moreover, these compounds were evaluated in vitro for their anticancer activity using ROS assays, Real-Time PCR, Western blots, flow cytometry, and cell cycle assays. RESULTS As a result of our investigation, it was determined that the extract significantly reduced the viability of cancerous cells while remaining harmless to normal cells. The combination of BPSE and VCR also resulted in synergistic effects. BPSE and/or BPSE-VCR treatment increased the intracellular ROS of MCF-7 cells by over twofold. Moreover, the IC30 of BPSE (100 μg/ml) significantly increased the BAX/BCL-2 and P53 gene expression while reducing the expression of the MYC gene. Moreover, treated cells were arrested in the G2 phase of the cell cycle. The BPSE-VCR combination synergistically reduced the NF-κB and increased the Caspase-7 proteins' expression. The percent of apoptosis in the cells treated with the extract, VCR, and their combination was 27, 11, and 50, respectively. CONCLUSIONS The present study demonstrated the anticancer activity of the BPSE and its potential for application in combination therapy with VCR.
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Affiliation(s)
| | - Ahmad Ismaili
- Department of Plant Production and Genetic Engineering, Faculty of Agriculture, Lorestan University, Khorramabad, Iran Iran
| | - Saeed Esmaeili-Mahani
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Esmaeil Ebrahimie
- La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne, VIC 3086, Australia
| | - Evelin Loit
- Chair of Crop Science and Plant Biology, Institute of Agricultural and Environmental Sciences, Estonian University of Life Sciences, Tartu, Estonia
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27
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Abdelrahman AM, Mohammed AA, Badawy MMM, El Bassuony WI. Orange peels and Chlorella vulgaris supplementation ameliorate gamma radiation-induced oxidative stress by regulating TGF-β and NOX2/NOX4 signaling pathways. Cell Biochem Funct 2023; 41:1263-1274. [PMID: 37756035 DOI: 10.1002/cbf.3861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/26/2023] [Accepted: 09/14/2023] [Indexed: 09/28/2023]
Abstract
Numerous studies revealed that Chlorella vulgaris and orange peels are potential sources for many valuable compounds such as flavonoids, which are natural polyphenols with antioxidant capacities that lessen oxidative stress via suppressing ROS levels. Thus, this study was designed to investigate their radioprotective efficiency either alone or in combination as natural food supplements. Sixty-four male Albino rats were divided into eight groups (n = 8) as follows: control, orange peel (10% in diet), C. vulgaris (1% in diet), orange peel + C. vulgaris, gamma irradiated (2Gy twice per week up to 8Gy), orange peel + gamma irradiation, C. vulgaris + gamma irradiation, and orange peel + C. vulgaris + gamma irradiation. After the experiment, blood serums were collected for biochemical analysis, whole bloods were collected for blood picture, bone marrows were collected for GSH, MDA, TGF-β, NOX2 and NOX4, and liver tissues were collected for histopathological evaluation. Current study revealed that exposure to gamma irradiation induced a significant disturbance in liver function markers (ALT and AST), kidney function markers (urea and creatinine), cholesterol and triglycerides levels in serum. In addition, a significant decrease in WBCs, RBCs, PLT, and Hb in blood of irradiated rats. Moreover, a significant elevation in TGF-β, NOX2, NOX4 activities, and MDA level, while showed a marked decrease in GSH concentration. Furthermore, hepatic inflammation appeared in the histopathological examination. Orange peels or C. vulgaris treatments showed acceptable amelioration in all measured parameters, combination between orange peels and C. vulgaris showed statistically significant additive amelioration in radiation induced disturbance.
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Affiliation(s)
- Abour M Abdelrahman
- Home Economic Department, Faculty of Specific Education, Ain Shams University, Cairo, Egypt
| | - Asmaa A Mohammed
- Department of Medical and Radiological Research, Nuclear Materials Authority, Cairo, Egypt
| | - Monda M M Badawy
- Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Walaa I El Bassuony
- Medical and Radiological Department, Nuclear Materials Authority, Cairo, Egypt
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28
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Yao D, Li M, Wang K, Jin S, Zeng W, Liao Z, Chen E, Liang Y, Xing T, Wen G, Liang C, Su K, Lu S, Che Z, Li Y, Huang L. Emodin ameliorates matrix degradation and apoptosis in nucleus pulposus cells and attenuates intervertebral disc degeneration through LRP1 in vitro and in vivo. Exp Cell Res 2023; 432:113794. [PMID: 37741491 DOI: 10.1016/j.yexcr.2023.113794] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/17/2023] [Accepted: 09/18/2023] [Indexed: 09/25/2023]
Abstract
Low back pain (LBP) is the leading cause of disability worldwide, with a strong correlation to intervertebral disc degeneration (IDD). Inflammation-induced extracellular matrix (ECM) degradation plays a major role in IDD's progression. Emodin, known for its anti-inflammatory effects and ability to inhibit ECM degradation in osteoarthritis, but its role in IDD is unclear. Our study aimed to explore emodin's role and mechanisms on IDD both in vivo and in vitro. We discovered that emodin positively regulated anabolic markers (COL2A1, aggrecan) and negatively impacted catabolic markers (MMP3, MMP13) in nucleus pulposus cells, while also inhibiting cell apoptosis under inflammation environment. We revealed that emodin inhibits inflammation-induced NF-ĸB activation by suppressing the degradation of LRP1 via the proteasome pathway. Additionally, LRP1 was validated as essential to emodin's regulation of ECM metabolism and apoptosis, both in vitro and in vivo. Ultimately, we demonstrated that emodin effectively alleviates IDD in a rat model. Our findings uncover the novel pathway of emodin inhibiting ECM degradation and apoptosis through the inhibition of NF-κB via LRP1, thus alleviating IDD. This study not only broadens our understanding of emodin's role and mechanism in IDD treatment but also guides future therapeutic interventions.
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Affiliation(s)
- Dengbo Yao
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Ming Li
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Kun Wang
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Song Jin
- Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Weike Zeng
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Zhuangyao Liao
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Enming Chen
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yuwei Liang
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Tong Xing
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Guoming Wen
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Changchun Liang
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Kaihui Su
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Shixin Lu
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
| | - Zhen Che
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yuxi Li
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Lin Huang
- Department of Orthopedics Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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Liu K, Cao Z, Huang S, Kong F. Mechanism underlying the effect of Pulsatilla decoction in hepatocellular carcinoma treatment: a network pharmacology and in vitro analysis. BMC Complement Med Ther 2023; 23:405. [PMID: 37950195 PMCID: PMC10636957 DOI: 10.1186/s12906-023-04244-w] [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: 03/07/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Currently, hepatocellular carcinoma (HCC) is associated with a poor prognosis. Moreover, there exist limited strategies for treating HCC. Pulsatilla decoction (PD), a traditional Chinese medicine formula, has been used to treat inflammatory bowel disease and several cancer types. Accordingly, we explored the mechanism of PD in HCC treatment via network pharmacology and in vitro experiments. METHODS Online databases were searched for gene data, active components, and potential target genes associated with HCC development. Subsequently, bioinformatics analysis was performed using protein-protein interaction and Network Construction and Kyoto Encyclopedia of Genes and Genomes (KEGG) to screen for potential anticancer components and therapeutic targets of PD. Finally, the effect of PD on HCC was further verified by in vitro experiments. RESULTS Network pharmacological analysis revealed that 65 compounds and 180 possible target genes were associated with the effect of PD on HCC. These included PI3K, AKT, NF-κB, FOS, and NFKBIA. KEGG analysis demonstrated that PD exerted its effect on HCC mainly via the PI3K-AKT, IL-17, and TNF signaling pathways. Cell viability and cell cycle experiments revealed that PD could significantly inhibit cancer cell proliferation and kill HCC cells by inducing apoptosis. Furthermore, western blotting confirmed that apoptosis was mediated primarily via the PI3K-AKT, IL-17, and TNF signaling pathways. CONCLUSION To the best of our knowledge, this is the first study to elucidate the molecular mechanism and potential targets of PD in the treatment of HCC using network pharmacology.
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Affiliation(s)
- Kuijie Liu
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhenyu Cao
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Siqi Huang
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Fanhua Kong
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
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30
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Gunay G, Maier KN, Hamsici S, Carvalho F, Timog TA, Acar H. Peptide aggregation-induced immunogenic cell death in a breast cancer spheroid model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.31.565012. [PMID: 37961293 PMCID: PMC10635027 DOI: 10.1101/2023.10.31.565012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Utilizing multicellular aggregates (spheroids) for in vitro cancer research offers a physiologically relevant model that closely mirrors the intricate tumor microenvironment, capturing properties of solid tumors such as cell interactions and drug resistance. In this research, we investigated the Peptide-Aggregation Induced Immunogenic Response (PAIIR), an innovative method employing engineered peptides we designed specifically to induce immunogenic cell death (ICD). We contrasted PAIIR-induced ICD with standard ICD and non-ICD inducer chemotherapeutics within the context of three-dimensional breast cancer tumor spheroids. Our findings reveal that PAIIR outperforms traditional chemotherapeutics in its efficacy to stimulate ICD. This is marked by the release of key damage-associated molecular patterns (DAMPs), which bolster the phagocytic clearance of dying cancer cells by dendritic cells (DCs) and, in turn, activate powerful anti-tumor immune responses. Additionally, we observed that PAIIR results in elevated dendritic cell activation and increased antitumor cytokine presence. This study not only showcases the utility of tumor spheroids for efficient high-throughput screening but also emphasizes PAIIR's potential as a formidable immunotherapeutic strategy against breast cancer, setting the stage for deeper exploration and potential clinical implementation.
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31
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Yang X, Man D, Zhao P, Li X. Identification of the therapeutic mechanism of the saffron crocus on glioma through network pharmacology and bioinformatics analysis. Med Oncol 2023; 40:296. [PMID: 37691037 DOI: 10.1007/s12032-023-02142-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023]
Abstract
Saffron crocus is a herbal medicine of traditional Tibetan medicine (TTM). Saffron extract has been indicated to inhibit tumor cell growth and promote tumor cell apoptosis in a variety of cancers, including glioma, but the specific mechanism is not clear. To study the possible mechanism of saffron action on glioma, network pharmacology and bioinformatics analysis methods were used in this study. We used the online database to obtain the active ingredients of saffron and their targets. Glioma-related targets were also acquired from online database. We intersected drug targets with glioma-related targets and conducted PPI network analysis to obtain network core genes. Then, we obtained RNA-seq data from The Cancer Genome Atlas (TCGA) database for glioma patients. Through different expression analysis and lasso regression, further screening of core genes in the network was conducted, and a prognostic model was established. The sample was divided into two groups with high and low risk using this model. The RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) database were used to further validate our prediction model. Then, we explored the difference in pathways enrichment between high-risk patients and low-risk patients and calculated the difference in immune microenvironment between the two groups. Finally, we used scRNA-seq data in the CGGA database to analyze the cell types in which the model gene is mainly enriched and predicted the cell types which saffron effected on.
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Affiliation(s)
- Xiaobing Yang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Dulegeqi Man
- Department of Neurosurgery, International Mongolia Hospital of Inner Mongolia, Hohhot, China
| | - Peng Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China.
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China.
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China.
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China.
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32
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Ding Y, Chen Q. The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury. Mol Neurobiol 2023; 60:5292-5308. [PMID: 37286724 DOI: 10.1007/s12035-023-03411-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
Spinal cord injury (SCI) is a type of central nervous system trauma that can lead to severe nerve injury. Inflammatory reaction after injury is an important pathological process leading to secondary injury. Long-term stimulation of inflammation can further deteriorate the microenvironment of the injured site, leading to the deterioration of neural function. Understanding the signaling pathways that regulate responses after SCI, especially inflammatory responses, is critical for the development of new therapeutic targets and approaches. Nuclear transfer factor-κB (NF-κB) has long been recognized as a key factor in regulating inflammatory responses. The NF-κB pathway is closely related to the pathological process of SCI. Inhibition of this pathway can improve the inflammatory microenvironment and promote the recovery of neural function after SCI. Therefore, the NF-κB pathway may be a potential therapeutic target for SCI. This article reviews the mechanism of inflammatory response after SCI and the characteristics of NF-κB pathway, emphasizing the effect of inhibiting NF-κB on the inflammatory response of SCI to provide a theoretical basis for the biological treatment of SCI.
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Affiliation(s)
- Yi Ding
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
- The Affiliated Ganzhou Hospital of Nanchang University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
| | - Qin Chen
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
- The Affiliated Ganzhou Hospital of Nanchang University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
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33
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He J, Zhang HP. Research progress on the anti-tumor effect of Naringin. Front Pharmacol 2023; 14:1217001. [PMID: 37663256 PMCID: PMC10469811 DOI: 10.3389/fphar.2023.1217001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Naringin is a kind of natural dihydro flavone, which mainly exists in citrus fruits of the Rutaceae family, as well as traditional Chinese medicines such as trifoliate orange, fingered citron, exocarpium citri grandis, and rhizoma dynamite. Modern pharmacological studies have shown that Naringin has excellent anti-tumor activity. Through reviewing the relevant literature at home and abroad in recent years, we summarized the pharmacological mechanism of Naringin to play an anti-cancer role in blocking tumor cell cycle, inhibiting tumor cell proliferation, inducing tumor cell apoptosis, inhibiting tumor cell invasion and metastasis, inducing tumor cell autophagy, reversing tumor cell drug resistance and enhancing chemotherapeutic drug sensitivity, as well as anti-inflammatory to prevent canceration, alleviate Adverse drug reaction of chemotherapy, activate and strengthen immunity, It provides theoretical basis and reference basis for further exploring the anticancer potential of Naringin and its further development and utilization.
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Affiliation(s)
- Jing He
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hui-Ping Zhang
- Oncology Department, Jinan Traditional Chinese Medicine Hospital, Jinan, China
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34
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Wu XY, Xu WW, Huan XK, Wu GN, Li G, Zhou YH, Najafi M. Mechanisms of cancer cell killing by metformin: a review on different cell death pathways. Mol Cell Biochem 2023; 478:197-214. [PMID: 35771397 DOI: 10.1007/s11010-022-04502-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/08/2022] [Indexed: 01/17/2023]
Abstract
Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.
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Affiliation(s)
- Xiao-Yu Wu
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Wen-Wen Xu
- Department of Gynaecology, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China
| | - Xiang-Kun Huan
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Guan-Nan Wu
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Gang Li
- Department of General Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Yu-Hong Zhou
- Digestive Endoscopy Center, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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35
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Moslehi M, Rezaei S, Talebzadeh P, Ansari MJ, Jawad MA, Jalil AT, Rastegar-Pouyani N, Jafarzadeh E, Taeb S, Najafi M. Apigenin in cancer therapy: Prevention of genomic instability and anticancer mechanisms. Clin Exp Pharmacol Physiol 2023; 50:3-18. [PMID: 36111951 DOI: 10.1111/1440-1681.13725] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/18/2022] [Accepted: 09/14/2022] [Indexed: 12/13/2022]
Abstract
The incidence of cancer has been growing worldwide. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long-term adverse effects of cancer therapy, for example, second primary malignancies. Moreover, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb-derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant-derived molecule with attractive properties for chemoprevention, for instance, promising anti-tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anticancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed.
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Affiliation(s)
- Masoud Moslehi
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sepideh Rezaei
- Department of Chemistry, University of Houston, Houston, Texas, USA
| | - Pourya Talebzadeh
- Student Research Committee, Tehran Medical Faculty, Islamic Azad University, Tehran, Iran
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj, Saudi Arabia
| | | | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, Iraq
| | - Nima Rastegar-Pouyani
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Emad Jafarzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran.,Medical Biotechnology Research Center, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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36
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Cohen AO, Woo SH, Zhang J, Cho J, Ruiz ME, Gong J, Du R, Yarygina O, Jafri DZ, Bachelor MA, Finlayson MO, Soni RK, Hayden MS, Owens DM. Tbc1d10c is a selective, constitutive suppressor of the CD8 T-cell anti-tumor response. Oncoimmunology 2022; 11:2141011. [PMID: 36338148 PMCID: PMC9635554 DOI: 10.1080/2162402x.2022.2141011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cancer immunotherapy approaches target signaling pathways that are highly synonymous between CD4 and CD8 T-cell subsets and, therefore, often stimulate nonspecific lymphocyte activation, resulting in cytotoxicity to otherwise healthy tissue. The goal of our study was to identify intrinsic modulators of basic T lymphocyte activation pathways that could discriminately bolster CD8 anti-tumor effector responses. Using a Tbc1d10c null mouse, we observed marked resistance to a range of tumor types conferred by Tbc1d10c deficiency. Moreover, tumor-bearing Tbc1d10c null mice receiving PD-1 or CTLA-4 monotherapy exhibited a 33% or 90% cure rate, respectively. While Tbc1d10c was not expressed in solid tumor cells, Tbc1d10c disruption selectively augmented CD8 T-cell activation and cytotoxic effector responses and adoptive transfer of CD8 T cells alone was sufficient to recapitulate Tbc1d10c null tumor resistance. Mechanistically, Tbc1d10c suppressed CD8 T-cell activation and anti-tumor function by intersecting canonical NF-κB pathway activation via regulation of Map3k3-mediated IKKβ phosphorylation. Strikingly, none of these cellular or molecular perturbations in the NF-κB pathway were featured in Tbc1d10c null CD4 T cells. Our findings identify a Tbc1d10c-Map3k3-NF-κB signaling axis as a viable therapeutic target to promote CD8 T-cell anti-tumor immunity while circumventing CD4 T cell-associated cytotoxicity and NF-κB activation in tumor cells.
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Affiliation(s)
- Adrienne O. Cohen
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA
| | - Seung-Hyun Woo
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Discovery Biology Division, Velia Therapeutics, San Diego, CA, USA
| | - Junya Zhang
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA
| | - Jiyoon Cho
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Global Safety Assurance, Reckitt Benckiser Inc., Montvale, NJ, USA
| | - Marlon E. Ruiz
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Olink Proteomics, Los Angeles, CA90045, USA
| | - Jianli Gong
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Processing Cell Sciences, Merck & Co., Inc, Kenilworth, NJ, USA
| | - Rong Du
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA
| | - Olga Yarygina
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA
| | - Danya Z. Jafri
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA
| | - Michael A. Bachelor
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Boston Scientific, Center for Biological Innovation, Global Preclinical Sciences, Marlborough, MA, USA
| | - Michael O. Finlayson
- Department of Systems Biology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY, USA,Simons Foundation, New York, NY10010, USA
| | - Rajesh K. Soni
- Proteomics & Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY10032, USA
| | - Matthew S. Hayden
- Department of Surgery, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - David M. Owens
- Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY10032, USA,Department of Pathology & Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY, USA,CONTACT David M. Owens Russ Berrie Medical Science Pavilion, 1150 St. Nicholas Ave., Room 312A, New York, NY10032
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37
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Xu C, Shang Z, Najafi M. Lung Pneumonitis and Fibrosis in Cancer Therapy: A Review on Cellular and Molecular Mechanisms. Curr Drug Targets 2022; 23:1505-1525. [PMID: 36082868 DOI: 10.2174/1389450123666220907144131] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/05/2022] [Accepted: 08/02/2022] [Indexed: 01/25/2023]
Abstract
Fibrosis and pneumonitis are the most important side effects of lung tissue following cancer therapy. Radiotherapy and chemotherapy by some drugs, such as bleomycin, can induce pneumonitis and fibrosis. Targeted therapy and immunotherapy also may induce pneumonitis and fibrosis to a lesser extent compared to chemotherapy and radiotherapy. Activation of lymphocytes by immunotherapy or infiltration of inflammatory cells such as macrophages, lymphocytes, neutrophils, and mast cells following chemo/radiation therapy can induce pneumonitis. Furthermore, the polarization of macrophages toward M2 cells and the release of anti-inflammatory cytokines stimulate fibrosis. Lung fibrosis and pneumonitis may also be potentiated by some other changes such as epithelial-mesenchymal transition (EMT), oxidative stress, reduction/oxidation (redox) responses, renin-angiotensin system, and the upregulation of some inflammatory mediators such as a nuclear factor of kappa B (NF-κB), inflammasome, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Damages to the lung vascular system and the induction of hypoxia also can induce pulmonary injury following chemo/radiation therapy. This review explains various mechanisms of the induction of pneumonitis and lung fibrosis following cancer therapy. Furthermore, the targets and promising agents to mitigate lung fibrosis and pneumonitis will be discussed.
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Affiliation(s)
- Chaofeng Xu
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China
| | - Zhongtu Shang
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China
| | - Masoud Najafi
- Medical Technology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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38
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Guan C, Zhou X, Li H, Ma X, Zhuang J. NF-κB inhibitors gifted by nature: The anticancer promise of polyphenol compounds. Biomed Pharmacother 2022; 156:113951. [DOI: 10.1016/j.biopha.2022.113951] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
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39
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Du S, Liu Y, Yuan Y, Wang Y, Chen Y, Wang S, Chi Y. Advances in the study of HSP70 inhibitors to enhance the sensitivity of tumor cells to radiotherapy. Front Cell Dev Biol 2022; 10:942828. [PMID: 36036010 PMCID: PMC9399644 DOI: 10.3389/fcell.2022.942828] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
The 70 kDa heat shock protein (HSP70) is one of the most conserved proteins and a ubiquitous molecular chaperone that plays a role in the folding, remodeling, and degradation of various proteins to maintain proteostasis. It has been shown that HSP70 is abundantly expressed in cancer and enhances tumor resistance to radiotherapy by inhibiting multiple apoptotic pathways, such as interfering with the cellular senescence program, promoting angiogenesis, and supporting metastasis. Thus, HSP70 provides an effective target for enhancing the effects of radiation therapy in the clinical management of cancer patients. Inhibition of HSP70 enhances the radiation-induced tumor-killing effect and thus improves the efficacy of radiotherapy. This article reviews the sensitivity of Hsp70 and its related inhibitors to radiotherapy of tumor cells.
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Affiliation(s)
- Sihan Du
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Ying Liu
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Yuan Yuan
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yuran Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yanfang Chen
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Shuai Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
| | - Yuhua Chi
- Department of General Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
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Abstract
Cardiac remodelling is characterized by abnormal changes in the function and morphological properties such as diameter, mass, normal diameter of cavities, heart shape, fibrosis, thickening of vessels and heart layers, cardiomyopathy, infiltration of inflammatory cells, and some others. These damages are associated with damage to systolic and diastolic abnormalities, damage to ventricular function, and vascular remodelling, which may lead to heart failure and death. Exposure of the heart to radiation or anti-cancer drugs including chemotherapy drugs such as doxorubicin, receptor tyrosine kinase inhibitors (RTKIs) such as imatinib, and immune checkpoint inhibitors (ICIs) can induce several abnormal changes in the heart structure and function through the induction of inflammation and fibrosis, vascular remodelling, hypertrophy, and some others. This review aims to explain the basic mechanisms behind cardiac remodelling following cancer therapy by different anti-cancer modalities.
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Ling Q, Wu S, Liao X, Liu C, Chen Y. Anesthetic propofol enhances cisplatin-sensitivity of non-small cell lung cancer cells through N6-methyladenosine-dependently regulating the miR-486-5p/RAP1-NF-κB axis. BMC Cancer 2022; 22:765. [PMID: 35836137 PMCID: PMC9281112 DOI: 10.1186/s12885-022-09848-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/30/2022] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Drug resistance is a considerable challenge for chemotherapy in non-small cell lung cancer (NSCLC). Propofol, a commonly used intravenous anesthetics, has been reported to suppress the malignancy of various cancers. However, the effects of propofol on cisplatin (DDP) sensitivity in NSCLC and its molecular mechanisms have not been clearly clarified yet, and the present study aimed to resolve this problem. METHODS NSCLC cells were co-treated with propofol and DDP, Cell Counting kit-8 assay, colony formation assay and flow cytometry were conducted to test the role of propofol in regulating DDP-resistance in NSCLC. Next, through conducting quantitative real-time polymerase chain reaction, dual-luciferase gene reporter system and western blot, the responsible molecular axis in propofol regulating the DDP sensitivity in NSCLC was uncovered, and the function verification experiments were performed by transfection with the inhibitors or small interfering RNAs of those molecules. RESULTS Propofol suppressed cell viability, colony formation ability, tumorigenesis, and promoted cell apoptosis to enhance DDP-sensitivity in NSCLC in vitro and in vivo. Propofol increased miR-486-5p level in NSCLC cells and xenograft tumors tissues in a N6-methyladenosine (m6A)-dependent manner, thus inactivating the Ras-associated protein1 (RAP1)-NF-kappaB (NF-κB) axis. Propofol regulated the miR-486-5p/RAP1-NF-κB axis to improve DDP-sensitivity in NSCLC. CONCLUSIONS Taken together, this study firstly investigates the detailed molecular mechanisms by which propofol enhanced DDP-sensitivity in NSCLC cells, and a novel m6A-dependent miR-486-5p/RAP1-NF-κB axis is identified to be closely associated with the process.
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Affiliation(s)
- Quan Ling
- The First Department of Anesthesia, Zhongshan City People's Hospital, No.2, Sunwen East Road, Shiqi District, Zhongshan, 528400, China
| | - Shaoyong Wu
- Department of Anesthesiology, cancer prevention and treatment center, Sun Yat Sen University, Guangzhou, 510060, China
| | - Xiaozu Liao
- The First Department of Anesthesia, Zhongshan City People's Hospital, No.2, Sunwen East Road, Shiqi District, Zhongshan, 528400, China
| | - Chiyi Liu
- The First Department of Anesthesia, Zhongshan City People's Hospital, No.2, Sunwen East Road, Shiqi District, Zhongshan, 528400, China
| | - Yong Chen
- The First Department of Anesthesia, Zhongshan City People's Hospital, No.2, Sunwen East Road, Shiqi District, Zhongshan, 528400, China.
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Cellular Damage in the Target and Out-Of-Field Peripheral Organs during VMAT SBRT Prostate Radiotherapy: An In Vitro Phantom-Based Study. Cancers (Basel) 2022; 14:cancers14112712. [PMID: 35681692 PMCID: PMC9179488 DOI: 10.3390/cancers14112712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/18/2022] [Accepted: 05/27/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary New developments show that patients with prostate cancer can benefit from radiotherapy delivered with a hypo-fractionated regimen. The aim of our study was to investigate the effect of hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer on out-of-field organs. We used a humanoid phantom to irradiate prostate cells in conditions similar to patient therapy, using SBRT planning. Our results show that radiation doses in the location of the intestine and lung resulted in significantly higher radiation doses than the further locations. We observed a high radiotoxic effect in the cells irradiated in the prostate, and a small increase in DNA damage and cell killing in the intestine location. Gene expression analysis revealed significant enrichment of the biological processes related to the radiation response in the prostate. In the lung and thyroid, the enrichment of several gene groups was revealed, however the processes were not clearly related to the response to radiation. Our study provides extensive data on out-of-field safety of prostate SBRT. Abstract Hypo-fractionated stereotactic body radiation therapy (SBRT) is an effective treatment for prostate cancer (PCa). Although many studies have investigated the effects of SBRT on the prostate and adjacent organs, little is known about the effects further out-of-field. The aim of this study was to investigate, both in vitro and in a quasi-humanoid phantom, the biological effects (using a dose-scaling approach) of radiation in the out-of-field peripheral organs delivered by 6 MV volumetric modulated arc therapy (VMAT) SBRT in a prostate cancer model. Healthy prostate cells were irradiated in a phantom at locations corresponding to the prostate, intestine, lung, thyroid, and brain. Seven 10 Gy fractions of VMAT SBRT were delivered to the target in a single session without intermission (scaled-up method). Radiochromic films were used to measure the doses. The radiobiological response was assessed by measuring DNA breaks, the cell survival fraction, and differences in gene expression profile. Our results showed a strong, multiparametric radiobiological response of the cells in the prostate. Outside of the radiation field, the highest doses were observed in the intestine and lung. A small increase (not statistically significant) in DNA damage and cell death was observed in the intestines. Several gene groups (cell cycle, DNA replication) were depleted in the lung and thyroid (DNA replication, endocytosis), but further analysis revealed no changes in the relevant biological processes. This study provides extensive evidence of the types and extent of radiobiological responses during VMAT SBRT in a prostate cancer model. Additional research is needed to determine whether the radiobiological effects observed in the peripheral organs are validated in a clinical context.
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Costantino M, Corno C, Colombo D, Perego P. Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules. Front Pharmacol 2022; 13:889816. [PMID: 35685638 PMCID: PMC9170941 DOI: 10.3389/fphar.2022.889816] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/06/2022] [Indexed: 01/14/2023] Open
Abstract
Curcumin and related compounds are known for the large spectrum of activities. The chemical features of these compounds are important for their biological effects with a key role for the thiol-reactive α−β unsaturated carbonyl groups. Curcumin derivatives may overcome the limitation of the bioavailability of the parent compound, while maintaining the key chemical features responsible for biological activities. Curcumin and related compounds show anti-viral, anti-fungal, anti-microbial and anti-tumor activities. The therapeutic effects of curcumin, used as a supplement in cancer therapy, have been documented in various cancer types, in which inhibition of cell growth and survival pathways, induction of apoptosis and other cell death pathways have been reported. Curcumin-induced apoptosis has been linked both to the intrinsic and extrinsic apoptotic pathways. Necroptosis has also been involved in curcumin-induced toxicity. Among curcumin-induced effects, ferroptosis has also been described. The mechanism of curcumin toxicity can be triggered by reactive oxygen species-mediated endoplasmic reticulum stress. Curcumin targets have been identified in the context of the ubiquitin-proteasome system with evidence of inhibition of the proteasome proteolytic activities and cellular deubiquitinases. Curcumin has recently been shown to act on the tumor microenvironment with effects on cancer-associated fibroblasts and immune cells. The related product caffeic acid phenethyl ester has shown promising preclinical results with an effect on the inflammatory microenvironment. Here, we review the mechanisms underlying curcumin and derivatives toxicity towards cancer cells with particular emphasis on cell death pathways and the ubiquitin-proteasome system.
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Affiliation(s)
- Matteo Costantino
- Unit of Molecular Pharmacology, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Cristina Corno
- Unit of Molecular Pharmacology, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Diego Colombo
- Department of Medical Biotechnology and Translational Medicine, University of Milano, Milan, Italy
| | - Paola Perego
- Unit of Molecular Pharmacology, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- *Correspondence: Paola Perego,
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Hu Y, Xu R, Ma J, Yan Z, Ma J. Curcumol enhances cisplatin sensitivity of gastric cancer: involvement of microRNA-7 and the nuclear factor-kappa B/snail family transcriptional repressor 1 axis. Bioengineered 2022; 13:11668-11683. [PMID: 35510522 PMCID: PMC9275945 DOI: 10.1080/21655979.2022.2070975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Cisplatin is a primary chemotherapeutic drug for gastric cancer (GC) patients, but the drug resistance remains the leading cause of treatment failure and high mortality. Curcumol is a bioactive sesquiterpenoid that has reportedly been linked to cisplatin sensitivity in GC. This study focuses on the exact functions of curcumol in the cisplatin sensitivity of GC cells and the molecules of action. The curcumol treatment reduced the viability and migration and enhanced cisplatin sensitivity of GC cells in a dose-dependent manner. Microarray analysis suggested that microRNA-7 (miR-7) was the most upregulated miRNA in GC cells after curcumol treatment. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the curcumol-affected genes, including the target genes of miR-7, were enriched in the nuclear factor-kappa B (NF-κB) pathway, whose activity was suppressed after curcumol treatment. miR-7 was found to target and suppress RELA proto-oncogene (RELA, also known as p65), a NF-κB subunit. Downregulation of miR-7 blocked the sensitizing effects of curcumol on cells to cisplatin and led to increased expression of NF-κB p65 and snail family transcriptional repressor 1 (SNAIL). Further downregulation of RELA enhanced, whereas upregulation of SNAIL suppressed the sensitivity again. In summary, this study suggests that curcumol sensitizes GC cells to cisplatin via miR-7 and the suppression of the NF-κB/SNAIL axis. The findings may offer new thoughts that curcumol in combination with cisplatin might be a useful strategy for GC management.
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Affiliation(s)
- Ying Hu
- Department of Oncology, Nanjing Jiangning TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Ruitong Xu
- Department of Geriatric Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Jinxia Ma
- Department of Spleen and Stomach, Nanjing Jiangning TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Zhanpeng Yan
- Clinical Research Department of Chinese and Western Medicine, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, P.R. China
| | - Jun Ma
- Department of Oncology, Huai'an TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Huai'an, P.R. China
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Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin. Int J Mol Sci 2022; 23:ijms23073757. [PMID: 35409117 PMCID: PMC8999072 DOI: 10.3390/ijms23073757] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 02/01/2023] Open
Abstract
The flavonoid apigenin (4′,5,7-trihydroxyflavone), which is one of the most widely distributed phytochemicals in the plant kingdom, is one of the most thoroughly investigated phenolic components. Previous studies have attributed the physiological effects of apigenin to its anti-allergic, antibacterial, antidiabetic, anti-inflammatory, antioxidant, antiviral, and blood-pressure-lowering properties, and its documented anticancer properties have been attributed to the induction of apoptosis and autophagy, the inhibition of inflammation, angiogenesis, and cell proliferation, and the regulation of cellular responses to oxidative stress and DNA damage. The most well-known mechanism for the compound’s anticancer effects in human cancer cell lines is apoptosis, followed by autophagy, and studies have also reported that apigenin induces novel cell death mechanisms, such as necroptosis and ferroptosis. Therefore, the aim of this paper is to review the therapeutic potential of apigenin as a chemopreventive agent, as well as the roles of programmed cell death mechanisms in the compound’s chemopreventive properties.
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Abstract
Cancer resistance to therapy is a big issue in cancer therapy. Tumours may develop some mechanisms to reduce the induction of cell death, thus stimulating tumour growth. Cancer cells may show a low expression and activity of tumour suppressor genes and a low response to anti-tumour immunity. These mutations can increase the resistance of cancer cells to programmed cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, autophagic cell death, and some others. The upregulation of some mediators and transcription factors such as Akt, nuclear factor of κB, signal transducer and activator of transcription 3, Bcl-2, and others can inhibit cell death in cancer cells. Using adjuvants to induce the killing of cancer cells is an interesting strategy in cancer therapy. Nobiletin (NOB) is a herbal-derived agent with fascinating anti-cancer properties. It has been shown to induce the generation of endogenous ROS by cancer cells, leading to damage to critical macromolecules and finally cell death. NOB may induce the activity of p53 and pro-apoptosis mediators, and also inhibit the expression and nuclear translocation of anti-apoptosis mediators. In addition, NOB may induce cancer cell killing by modulating other mechanisms that are involved in programmed cell death mechanisms. This review aims to discuss the cellular and molecular mechanisms of the programmed cell death in cancer by NOB via modulating different types of cell death in cancer.
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Hu L, Li H, Zi M, Li W, Liu J, Yang Y, Zhou D, Kong QP, Zhang Y, He Y. Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development. Front Cell Dev Biol 2022; 10:822816. [PMID: 35252191 PMCID: PMC8890612 DOI: 10.3389/fcell.2022.822816] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/26/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a process that leads to a state of irreversible cell growth arrest induced by a variety of intrinsic and extrinsic stresses. Senescent cells (SnCs) accumulate with age and have been implicated in various age-related diseases in part via expressing the senescence-associated secretory phenotype. Elimination of SnCs has the potential to delay aging, treat age-related diseases and extend healthspan. However, once cells becoming senescent, they are more resistant to apoptotic stimuli. Senolytics can selectively eliminate SnCs by targeting the SnC anti-apoptotic pathways (SCAPs). They have been developed as a novel pharmacological strategy to treat various age-related diseases. However, the heterogeneity of the SnCs indicates that SnCs depend on different proteins or pathways for their survival. Thus, a better understanding of the underlying mechanisms for apoptotic resistance of SnCs will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear SnCs. In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.
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Affiliation(s)
- Li Hu
- Department of Geriatrics, The Second Affiliated Hospital of Hainan Medical University, Haikou, China.,State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.,College of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Huiqin Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Meiting Zi
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Wen Li
- Department of Endocrinology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Jing Liu
- Lab of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, China
| | - Yang Yang
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Daohong Zhou
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Yunxia Zhang
- Department of Geriatrics, The Second Affiliated Hospital of Hainan Medical University, Haikou, China.,College of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Yonghan He
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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Mortezaee K, Majidpoor J. (Im)maturity in Tumor Ecosystem. Front Oncol 2022; 11:813897. [PMID: 35145911 PMCID: PMC8821092 DOI: 10.3389/fonc.2021.813897] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/27/2021] [Indexed: 01/10/2023] Open
Abstract
Tumors have special features that make them distinct from their normal counterparts. Immature cells in a tumor mass and their critical contributions to the tumorigenesis will open new windows toward cancer therapy. Incomplete cellular development brings versatile and unique functionality in the cellular tumor ecosystem, such as what is seen for highly potential embryonic cells. There is evidence that maturation of certain types of cells in this ecosystem can recover the sensitivity of the tumor. Therefore, understanding more about the mechanisms that contributed to this immaturity will render new therapeutic approaches in cancer therapy. Targeting such mechanisms can be exploited as a supplementary to the current immunotherapeutic treatment schedules, such as immune checkpoint inhibitor (ICI) therapy. The key focus of this review is to discuss the impact of (im)maturity in cellular tumor ecosystems on cancer progression, focusing mainly on immaturity in the immune cell compartment of the tumor, as well as on the stemness of tumor cells.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
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Majidpoor J, Mortezaee K. Interleukin-6 in SARS-CoV-2 induced disease: Interactions and therapeutic applications. Biomed Pharmacother 2022; 145:112419. [PMID: 34781146 PMCID: PMC8585600 DOI: 10.1016/j.biopha.2021.112419] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/07/2021] [Accepted: 11/10/2021] [Indexed: 02/07/2023] Open
Abstract
Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease.
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Affiliation(s)
- Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Stati G, Passaretta F, Gindraux F, Centurione L, Di Pietro R. The Role of the CREB Protein Family Members and the Related Transcription Factors in Radioresistance Mechanisms. Life (Basel) 2021; 11:1437. [PMID: 34947968 PMCID: PMC8706059 DOI: 10.3390/life11121437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/02/2021] [Accepted: 12/16/2021] [Indexed: 02/05/2023] Open
Abstract
In the framework of space flight, the risk of radiation carcinogenesis is considered a "red" risk due to the high likelihood of occurrence as well as the high potential impact on the quality of life in terms of disease-free survival after space missions. The cyclic AMP response element-binding protein (CREB) is overexpressed both in haematological malignancies and solid tumours and its expression and function are modulated following irradiation. The CREB protein is a transcription factor and member of the CREB/activating transcription factor (ATF) family. As such, it has an essential role in a wide range of cell processes, including cell survival, proliferation, and differentiation. Among the CREB-related nuclear transcription factors, NF-κB and p53 have a relevant role in cell response to ionising radiation. Their expression and function can decide the fate of the cell by choosing between death or survival. The aim of this review was to define the role of the CREB/ATF family members and the related transcription factors in the response to ionising radiation of human haematological malignancies and solid tumours.
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Affiliation(s)
- Gianmarco Stati
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Francesca Passaretta
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Florelle Gindraux
- Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, Université Bourgogne Franche-Comté, 25030 Besançon, France;
- Service de Chirurgie Orthopédique, Traumatologique et Plastique, CHU, 25030 Besançon, France
| | - Lucia Centurione
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
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