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Ye B, Lin C, Huang H, Chen P, Liu X, Wang K, Zhang H, Liu J, Zhang C, Li L. Sophora compounds against non-small cell lung cancer: Research status and mechanisms. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156890. [PMID: 40414045 DOI: 10.1016/j.phymed.2025.156890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 05/11/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, characterized by dysregulated signaling pathways. Many Sophora compounds exhibit potential anti-NSCLC properties. However, the research status, particularly regarding the underlying mechanisms, remains fragmented. PURPOSE To review the research status as well as mechanisms of Sophora compounds against NSCLC. METHODS A systematic review was conducted on publications retrieved from PubMed, Web of Science and CNKI. The retrieval keywords are paired in various forms of "Sophora compound name" and "non-small cell lung cancer" (including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma). Only experimental (at cell or animal level) or clinical studies demonstrating therapeutic effects of Sophora compounds were included. RESULTS >52 Sophora compounds have demonstrated potential anti-NSCLC effects through various signaling pathways, primarily targeting apoptosis induction, cell cycle arrest, and metastasis suppression. Investigated signaling pathways mainly include apoptosis, PI3K/Akt/mTOR, MAPK, STAT3/NF-κB, and EGFR signaling. The expression of apoptotic caspases, Bcl-2, Bax, Akt, mTOR, PI3K, Erk, Jnk, p38, STAT3 and NF-κB is frequently assayed. Notably, most researches have focused on cell models of A549 and H1299, primarily on aforementioned signaling pathways at the protein level. CONCLUSION Many Sophora compounds, particularly flavonoids, show promise as multi-target agents against NSCLC. However, animal experiments and clinical evidence remain limited, and future studies could prioritize investigations on deeper molecular mechanisms, and on little-explored toxicology.
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Affiliation(s)
- Baibai Ye
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Cheng Lin
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Hao Huang
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Ping Chen
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Xinyu Liu
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Keke Wang
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Han Zhang
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Jiahui Liu
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Chenning Zhang
- Department of Pharmacy, Hubei University of Medicine, Xiangyang No 1 People's Hospital, Xiangyang 441100, China.
| | - Linfu Li
- Pharmacy College, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
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Wang HC, Wu PE, He WD, Chen CY, Zheng RQ, Pang YC, Wu LC, Cheng YX, Liu YQ. Centipeda minima extracts and the active sesquiterpene lactones have therapeutic efficacy in non-small cell lung cancer by suppressing Skp2/p27 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119277. [PMID: 39722328 DOI: 10.1016/j.jep.2024.119277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024]
Abstract
ETHNOPHAMACOLOGICAL RELEVANCE Centipeda minima (L.) A. Braun & Asch (C. minima) was applied to treat nasal allergy, headache, cough, and even nasopharyngeal carcinoma in traditional Chinese medicine. However, the underlying anticancer mechanisms of C. minima and its active components have not been systematically illustrated. AIM OF THE STUDY The study aims to examine the therapeutic efficacy of the ethanol extract of C. minima (ECM) and its active components in non-small cell lung cancer (NSCLC) and illustrate the underlying mechanisms. MATERIALS AND METHODS The main chemical components in the ethanol extract of C. minima (ECM) and the supercritical CO2 fluid extract of C. minima (CM-SFE) were determined by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The antitumor effects of ECM and CM-SFE were examined by using NSCLC cell xenografts. The flow cytometry, cell colony formation, wound-healing, transwell assay, and Western blotting were conducted to investigate the anticancer properties of ECM, CM-SFE, and these sesquiterpene lactones that abundantly distributed in these extracts. RESULTS We first determined that ECM contains high levels of sesquiterpene lactones. ECM can markedly induce cell cycle arrest and suppress migration and invasion of NSCLC cells. Mechanistically, ECM promoted proteasome-dependent degradation of Skp2 protein and induced the accumulation of its substrates p27; whereas Skp2 overexpression can attenuate the inhibitory effects of ECM on NSCLC proliferation and migration. Moreover, ECM at 200-600 mg/kg can significantly inhibit tumor growth and metastasis in A549-luciferase cell orthotopic xenografts by suppressing Skp2 expression. The sesquiterpene lactones that abundantly distributed in ECM, including 6-O-angeloylplenolin (6-OAP), arnicolide D (ArD) and arnicolide C (ArC), were also demonstrated to decrease Skp2 while increase p27 protein level, thereby significantly inducing cell cycle arrest and suppressing migration of NSCLC cells. Notably, CM-SFE, which mainly consisted of 6-OAP, ArD and ArC, exhibited much stronger anti-NSCLC activity than that of ECM in A549-luciferase cell orthotopic xenografts. CONCLUSION Our results demonstrate that the active components in C. minima possesses potential anti-NSCLC activities by suppressing Skp2/p27 signaling pathway, and these active sesquiterpene lactones can be further developed as potent Skp2 inhibitor to treat NSCLC.
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Affiliation(s)
- Han-Chen Wang
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Pei-En Wu
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Wen-Da He
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Chu-Ying Chen
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Rou-Qiao Zheng
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Yan-Chun Pang
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China
| | - Li-Chuan Wu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, 530004, China
| | - Yong-Xian Cheng
- Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Institute for Inheritance-Based Innovation of Chinese Medicine, Marshall Laboratory of Biomedical Engineering, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China.
| | - Yong-Qiang Liu
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, 510006, China; Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, China.
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Lee YS, Kwon RJ, Lee HS, Chung JH, Kim YS, Jeong HS, Park SJ, Lee SY, Kim T, Yoon SH. The Role of Pentacyclic Triterpenoids in Non-Small Cell Lung Cancer: The Mechanisms of Action and Therapeutic Potential. Pharmaceutics 2024; 17:22. [PMID: 39861671 PMCID: PMC11768946 DOI: 10.3390/pharmaceutics17010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action.
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Affiliation(s)
- Young-Shin Lee
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Ryuk Jun Kwon
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Hye Sun Lee
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Jae Heun Chung
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA;
| | - Yun Seong Kim
- Division of Pulmonology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea;
| | - Han-Sol Jeong
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Su-Jung Park
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Seung Yeon Lee
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Taehwa Kim
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Seong Hoon Yoon
- Division of Pulmonology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea;
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Zeng J, Chen Z, He Y, Jiang Z, Zhang Y, Dong Q, Chen L, Deng S, He Z, Li L, Li J, Shi J. A patent review of SCF E3 ligases inhibitors for cancer：Structural design, pharmacological activities and structure-activity relationship. Eur J Med Chem 2024; 278:116821. [PMID: 39232359 DOI: 10.1016/j.ejmech.2024.116821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/22/2024] [Accepted: 08/29/2024] [Indexed: 09/06/2024]
Abstract
Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, β-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, β-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, β-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments.
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Affiliation(s)
- Jing Zeng
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Zheng Chen
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Yuxin He
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Zhongliang Jiang
- Hematology Department, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Yi Zhang
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Qin Dong
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Liping Chen
- School of Comprehensive Health Management, Xihua University, Chengdu, 610039, China
| | - Sichun Deng
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Ziyou He
- School of Economics and Management, The University of Hong Kong, Hong Kong, 999077, China
| | - Ling Li
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China; Chengdu University of Traditional Chinese Medicine State Key Laboratory of Southwestern Chinese Medicine Resources, Sichuan, 611137, China.
| | - Jinqi Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Moralev A, Zenkova MA, Markov AV. Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome. ACS Pharmacol Transl Sci 2024; 7:3358-3384. [PMID: 39539268 PMCID: PMC11555519 DOI: 10.1021/acsptsci.4c00422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/13/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024]
Abstract
Pentacyclic triterpenoids (PTs) are a class of plant metabolites with a wide range of pharmacological activities, including strong antitumor potential against skin malignancies. By acting on multiple signaling pathways that control key cellular processes, PTs are able to exert complex effects on melanoma progression in vitro and in vivo. In this review, we have analyzed the works published in the past decade and devoted to the effects of PTs, both natural and semisynthetic, on cutaneous melanoma pathogenesis, including not only their direct action on melanoma cells but also their influence on the tumor microenvironment and abberant melanogenesis, often associated with melanoma aggressiveness. Special attention will be paid to the molecular basis of the pronounced antimelanoma potency of PTs, including a detailed consideration of the pathways sensitive to PTs in melanoma cells, as well as the reconstruction of the melanoma-related protein interactome of PTs using a network pharmacology approach based on previously published experimentally verified protein targets of PTs. The information collected on the primary targets of PTs was compiled in the Protein Interactome of PTs (PIPTs) database, freely available at http://www.pipts-db.ru/, which can be used to further optimize the mechanistic studies of PTs in the context of melanoma and other malignancies. By summarizing recent research findings, this review provides valuable information to scientists working in the fields related to the evaluation of melanoma pathogenesis and development of PTs-based drug candidates.
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Affiliation(s)
- Arseny
D. Moralev
- Institute of Chemical Biology and Fundamental
Medicine, Siberian Branch of the Russian
Academy of Sciences, 630090, Lavrent’ev avenue 8, Novosibirsk, Russia
| | - Marina A. Zenkova
- Institute of Chemical Biology and Fundamental
Medicine, Siberian Branch of the Russian
Academy of Sciences, 630090, Lavrent’ev avenue 8, Novosibirsk, Russia
| | - Andrey V. Markov
- Institute of Chemical Biology and Fundamental
Medicine, Siberian Branch of the Russian
Academy of Sciences, 630090, Lavrent’ev avenue 8, Novosibirsk, Russia
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Banerjee S, Banerjee S, Bishayee A, Da Silva MN, Sukocheva OA, Tse E, Casarcia N, Bishayee A. Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155858. [PMID: 39053249 DOI: 10.1016/j.phymed.2024.155858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 06/13/2024] [Accepted: 07/03/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. PURPOSE The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. METHODS Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. CONCLUSION BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound.
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Affiliation(s)
- Subhasis Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, West Bengal, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, West Bengal, India
| | | | - Milton Nascimento Da Silva
- Laboratory of Liquid Chromatography, Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; Chemistry Post-Graduation Program, Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; Pharmaceutical Science Post-Graduation Program, Institute of Health Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil
| | - Olga A Sukocheva
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Nicolette Casarcia
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Anupam Bishayee
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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Chen Z, Zhang J, Gao S, Jiang Y, Qu M, Gu J, Wu H, Nan K, Zhang H, Wang J, Chen W, Miao C. Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2. Cell Mol Life Sci 2024; 81:325. [PMID: 39079969 PMCID: PMC11335248 DOI: 10.1007/s00018-024-05348-3] [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: 03/24/2024] [Revised: 06/19/2024] [Accepted: 07/03/2024] [Indexed: 08/22/2024]
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.
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Affiliation(s)
- Zhaoyuan Chen
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Jie Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Shenjia Gao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Yi Jiang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Mengdi Qu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Jiahui Gu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Han Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Ke Nan
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Hao Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Jun Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Wankun Chen
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
- Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158# Gongyuan Dong Road, Shanghai, 201700, China.
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
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Odarenko KV, Zenkova MA, Markov AV. The Nexus of Inflammation-Induced Epithelial-Mesenchymal Transition and Lung Cancer Progression: A Roadmap to Pentacyclic Triterpenoid-Based Therapies. Int J Mol Sci 2023; 24:17325. [PMID: 38139154 PMCID: PMC10743660 DOI: 10.3390/ijms242417325] [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: 11/01/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Its high mortality is partly due to chronic inflammation that accompanies the disease and stimulates cancer progression. In this review, we analyzed recent studies and highlighted the role of the epithelial-mesenchymal transition (EMT) as a link between inflammation and lung cancer. In the inflammatory tumor microenvironment (iTME), fibroblasts, macrophages, granulocytes, and lymphocytes produce inflammatory mediators, some of which can induce EMT. This leads to increased invasiveness of tumor cells and self-renewal of cancer stem cells (CSCs), which are associated with metastasis and tumor recurrence, respectively. Based on published data, we propose that inflammation-induced EMT may be a potential therapeutic target for the treatment of lung cancer. This prospect is partially realized in the development of EMT inhibitors based on pentacyclic triterpenoids (PTs), described in the second part of our study. PTs reduce the metastatic potential and stemness of tumor cells, making PTs promising candidates for lung cancer therapy. We emphasize that the high diversity of molecular mechanisms underlying inflammation-induced EMT far exceeds those that have been implicated in drug development. Therefore, analysis of information on the relationship between the iTME and EMT is of great interest and may provide ideas for novel treatment approaches for lung cancer.
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Affiliation(s)
- Kirill V. Odarenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (K.V.O.); (M.A.Z.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Marina A. Zenkova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (K.V.O.); (M.A.Z.)
| | - Andrey V. Markov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (K.V.O.); (M.A.Z.)
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Yang ZY, Zhao YW, Xue JR, Guo R, Zhao Z, Liu HD, Ren ZG, Shi M. Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis. World J Gastroenterol 2023; 29:5974-5987. [PMID: 38130998 PMCID: PMC10731152 DOI: 10.3748/wjg.v29.i45.5974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/19/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.
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Affiliation(s)
- Zheng-Yan Yang
- Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan Province, China
| | - Yi-Wei Zhao
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, Henan Province, China
| | - Jing-Rui Xue
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, Henan Province, China
| | - Ran Guo
- Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan Province, China
| | - Zhi Zhao
- Department of Pathology, Henan University-affiliated Zhengzhou Yihe Hospital, Zhengzhou 450000, Henan Province, China
| | - Han-Di Liu
- Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan Province, China
| | - Zhi-Guang Ren
- Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan Province, China
- Key Laboratory of Clinical Resources Translation, The First Affiliated Hospital, Henan University, Kaifeng 475004, Henan Province, China
| | - Ming Shi
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
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Huang D, Wu PE, Chen ZJ, Pang YC, Xu ZW, Tan J, Jiang ZH, Yang BB, Zhan R, Xu H, Liu YQ. Ethanol Extract of Citrus grandis 'Tomentosa' Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non-Small Cell Lung Cancer. Mol Nutr Food Res 2023; 67:e2300061. [PMID: 37436082 DOI: 10.1002/mnfr.202300061] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 06/22/2023] [Indexed: 07/13/2023]
Abstract
SCOPE This study aims to investigate the anticancer properties of Citrus grandis 'Tomentosa' (CGT) in non-small cell lung cancer (NSCLC). METHODS AND RESULTS The ethanol extract of CGT (CGTE) is prepared by using anhydrous ethanol and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2-SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co-immunoprecipitation (co-IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway. CONCLUSION These findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.
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Affiliation(s)
- Da Huang
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Pei-En Wu
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zi-Jie Chen
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Yan-Chun Pang
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zi-Wei Xu
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jingbo Tan
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhi-Hua Jiang
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bing-Bing Yang
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ruoting Zhan
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Hui Xu
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Yong-Qiang Liu
- Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, China
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Choudhary N, Bawari S, Burcher JT, Sinha D, Tewari D, Bishayee A. Targeting Cell Signaling Pathways in Lung Cancer by Bioactive Phytocompounds. Cancers (Basel) 2023; 15:3980. [PMID: 37568796 PMCID: PMC10417502 DOI: 10.3390/cancers15153980] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Lung cancer is a heterogeneous group of malignancies with high incidence worldwide. It is the most frequently occurring cancer in men and the second most common in women. Due to its frequent diagnosis and variable response to treatment, lung cancer was reported as the top cause of cancer-related deaths worldwide in 2020. Many aberrant signaling cascades are implicated in the pathogenesis of lung cancer, including those involved in apoptosis (B cell lymphoma protein, Bcl-2-associated X protein, first apoptosis signal ligand), growth inhibition (tumor suppressor protein or gene and serine/threonine kinase 11), and growth promotion (epidermal growth factor receptor/proto-oncogenes/phosphatidylinositol-3 kinase). Accordingly, these pathways and their signaling molecules have become promising targets for chemopreventive and chemotherapeutic agents. Recent research provides compelling evidence for the use of plant-based compounds, known collectively as phytochemicals, as anticancer agents. This review discusses major contributing signaling pathways involved in the pathophysiology of lung cancer, as well as currently available treatments and prospective drug candidates. The anticancer potential of naturally occurring bioactive compounds in the context of lung cancer is also discussed, with critical analysis of their mechanistic actions presented by preclinical and clinical studies.
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Affiliation(s)
- Neeraj Choudhary
- Department of Pharmacognosy, GNA School of Pharmacy, GNA University, Phagwara 144 401, India
| | - Sweta Bawari
- Amity Institute of Pharmacy, Amity University, Noida 201 301, India
| | - Jack T. Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Dona Sinha
- Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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Jing J, Rui L, Junyuan S, Jinfeng Y, Zhihao H, Weiguo L, Zhenyu J. Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review. Front Pharmacol 2023; 14:1122008. [PMID: 37089937 PMCID: PMC10113621 DOI: 10.3389/fphar.2023.1122008] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
S-phase kinase-associated protein 2 (Skp2) is a substrate-specific adaptor in Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases and widely regarded as an oncogene. Therefore, Skp2 has remained as an active anticancer research topic since its discovery. Accordingly, the structure of Skp2 has been solved and numerous Skp2 inhibiting compounds have been identified. In this review, we would describe the structural features of Skp2, introduce the ubiquitination function of SCFSkp2, and summarize the diverse natural and synthetic Skp2 inhibiting compounds reported to date. The IC50 data of the Skp2 inhibitors or inhibiting compounds in various kinds of tumors at cellular levels implied that the cancer type, stage and pathological mechanisms should be taken into consideration when selecting Skp2-inhibiting compound for cancer treatment.
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Affiliation(s)
- Jia Jing
- Schools of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
| | - Li Rui
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Sun Junyuan
- Schools of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
| | - Yang Jinfeng
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
| | - Hong Zhihao
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
| | - Lu Weiguo
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Hangzhou, Zhejiang Province, China
- *Correspondence: Lu Weiguo, ; Jia Zhenyu,
| | - Jia Zhenyu
- Institute of Occupation Diseases, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
- *Correspondence: Lu Weiguo, ; Jia Zhenyu,
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Farooqi AA, Turgambayeva A, Tashenova G, Tulebayeva A, Bazarbayeva A, Kapanova G, Abzaliyeva S. Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010067. [PMID: 36615262 PMCID: PMC9822120 DOI: 10.3390/molecules28010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/02/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized our understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades. In this mini-review, we have attempted to provide a sophisticated compendium of regulatory role of betulinic acid in cancer chemoprevention. We have partitioned this multi-component review into different sections in which we summarized landmark research-works which highlighted betulinic acid mediated regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in the inhibition of cancer. In parallel, betulinic acid mediated regulation of signaling cascades and non-coding RNAs will be critically analyzed in cell culture and animal model studies. Better comprehension of the pharmaceutical features of betulinic acid and mapping of the existing knowledge gaps will be valuable in the translatability of preclinical studies into rationally designed clinical trials.
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Affiliation(s)
- Ammad Ahmad Farooqi
- Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 54000, Pakistan
- Correspondence:
| | - Assiya Turgambayeva
- Department of Public Health and Management, NJSC “Astana Medical University”, Astana 010000, Kazakhstan
| | - Gulnara Tashenova
- Asfendiyarov Kazakh National Medical University, Almaty 050040, Kazakhstan
- Scientific Center of Pediatrics and Pediatric Surgery, Almaty 050060, Kazakhstan
| | - Aigul Tulebayeva
- Asfendiyarov Kazakh National Medical University, Almaty 050040, Kazakhstan
- Scientific Center of Pediatrics and Pediatric Surgery, Almaty 050060, Kazakhstan
| | - Aigul Bazarbayeva
- Scientific Center of Pediatrics and Pediatric Surgery, Almaty 050060, Kazakhstan
| | - Gulnara Kapanova
- Scientific Center of Anti-Infectious Drugs, 75 al-Faraby Ave, Almaty 050040, Kazakhstan
- Al-Farabi Kazakh National University, 71 al-Farabi Ave, Almaty 050040, Kazakhstan
| | - Symbat Abzaliyeva
- Al-Farabi Kazakh National University, 71 al-Farabi Ave, Almaty 050040, Kazakhstan
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Chen H, Zheng M, Zhang W, Long Y, Xu Y, Yuan M. Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:6404853. [PMID: 36185084 PMCID: PMC9519343 DOI: 10.1155/2022/6404853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is known as one of the most lethal cancers, causing more than 1 million deaths annually worldwide. Therefore, the development of novel therapeutic drugs for NSCLC has become an urgent need. Herein, various mouse models provide great convenience not only for researchers but also for the development of antitumor drug. Meanwhile, TCM, as a valuable and largely untapped resource pool for modern medicine, provides research resources for the treatment of various diseases. Until now, cell-derived xenograft (CDX) model, patient-derived xenograft (PDX) model, syngeneic model, orthotopic model, humanized mouse model (HIS), and genetically engineered mouse models (GEMMs) have been reported in TCM evaluation. This review shows the role and current status of kinds of mouse models in antitumor research and summarizes the application progress of TCM including extracts, formulas, and isolated single molecules for NSCLC therapy in various mouse models; more importantly, it provides a theoretical exploration of what kind of mouse models is ideal for TCM efficacy evaluation in future. However, there are still huge challenges and limitations in the development of mouse models specifically for the TCM research, and none of the available models are perfectly matching the characteristics of TCM, which suppress the tumor growth through various mechanisms, especially by regulating immune function. Nevertheless, with fully functional immune system existing in syngeneic model and humanized mouse model (HIS), it is still suggested that these two models are more suitable for development of TCM especially for TCM extracts or formulas. Moreover, continued efforts are needed to generate more reliable mouse models to test TCM formulas in future research.
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Affiliation(s)
- Hongkui Chen
- Shanghai Lidebiotech Co. Ltd., Shanghai 201203, China
| | - Min Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenhui Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
| | - Yuan Long
- Shanghai Lidebiotech Co. Ltd., Shanghai 201203, China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
| | - Man Yuan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
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Tang Y, Guo Y. A Ubiquitin-Proteasome Gene Signature for Predicting Prognosis in Patients With Lung Adenocarcinoma. Front Genet 2022; 13:893511. [PMID: 35711913 PMCID: PMC9194557 DOI: 10.3389/fgene.2022.893511] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Dysregulation of the ubiquitin-proteasome system (UPS) can lead to instability in the cell cycle and may act as a crucial factor in both tumorigenesis and tumor progression. However, there is no established prognostic signature based on UPS genes (UPSGs) for lung adenocarcinoma (LUAD) despite their value in other cancers. Methods: We retrospectively evaluated a total of 703 LUAD patients through multivariate Cox and Lasso regression analyses from two datasets, the Cancer Genome Atlas (n = 477) and GSE31210 (n = 226). An independent dataset (GSE50081) containing 128 LUAD samples were used for validation. Results: An eight-UPSG signature, including ARIH2, FBXO9, KRT8, MYLIP, PSMD2, RNF180, TRIM28, and UBE2V2, was established. Kaplan-Meier survival analysis and time-receiver operating characteristic curves for the training and validation datasets revealed that this risk signature presented with good performance in predicting overall and relapsed-free survival. Based on the signature and its associated clinical features, a nomogram and corresponding web-based calculator for predicting survival were established. Calibration plot and decision curve analyses showed that this model was clinically useful for both the training and validation datasets. Finally, a web-based calculator (https://ostool.shinyapps.io/lungcancer) was built to facilitate convenient clinical application of the signature. Conclusion: An UPSG based model was developed and validated in this study, which may be useful as a novel prognostic predictor for LUAD.
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Affiliation(s)
- Yunliang Tang
- Department of Rehabilitation Medicine, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yinhong Guo
- Department of Oncology, Zhuji People's Hospital of Zhejiang Province, Zhuji, China
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Chen X, Lu S, Gong F, Sui X, Liu T, Wang T. Research on the synthesis of nanoparticles of betulinic acid and their targeting antitumor activity. J Biomed Mater Res B Appl Biomater 2022; 110:1789-1795. [PMID: 35179806 DOI: 10.1002/jbm.b.35036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022]
Abstract
Betulinic acid (BA), a natural pentacyclic lupine-type triterpene, has shown its prominent efficiency on the selective antitumor activity. However, its poor water solubility and bioavailability have limited its application. Herein, targeting nanoparticles were prepared to improve BA-based liposome (BL)'s restricted chemotherapeutic efficacy. Multi-layers membranes from the cancer cells were added as highly penetrative targeting ligands to functionalize the BA-based liposomes. In vitro experiments including the MTT assay and the fluorescence imaging of live/dead staining were adopted to prove its great inhibition in the growth of tumor cells. And it manifests that the antitumor efficacy of BL coated with cell membranes (BLCM) achieves nearly 4.3 times as that of BL under the same conditions in the MTT experiments. In addition, the fluorescence imaging stained with DAPI-FITC was applied to prove the targeting positioning effects on the BLCM. In a nutshell, the nanomedicine has good targeting antitumor efficacy and has great potential in being applied for the personalized cancer clinical treatment.
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Affiliation(s)
- Xuan Chen
- College of Chemistry, Chemical Engineering and Resources Utilization, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Shuting Lu
- College of Chemistry, Chemical Engineering and Resources Utilization, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Fengrong Gong
- College of Chemistry, Chemical Engineering and Resources Utilization, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Xiaoyu Sui
- College of Pharmacy, Qiqihar Medical University, Qiqihar, China
| | - Tingting Liu
- College of Pharmacy, Qiqihar Medical University, Qiqihar, China
| | - Ting Wang
- College of Chemistry, Chemical Engineering and Resources Utilization, Northeast Forestry University, Harbin, Heilongjiang, China
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Xing S, Nong F, Wang Y, Huang D, Qin J, Chen YF, He DH, Wu PE, Huang H, Zhan R, Xu H, Liu YQ. Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis. Pharmacol Res 2022; 176:106059. [PMID: 34998973 DOI: 10.1016/j.phrs.2022.106059] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 11/23/2022]
Abstract
Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treating a wide range of tumors; however, the direct targets of Bru and its anticancer mode of action remain unclear. In our study, 793 Bru-binding candidate proteins were identified by using a biotin-brusatol conjugate (Bio-Bru) followed by streptavidin-affinity pull down-based mass spectrometry. We found that Bru can directly bind to Skp1 and disrupt the interactions of Skp1 with the F-box protein Skp2, leading to the inhibition of the Skp2-SCF E3 ligase. Bru inhibited both proliferation and migration via promoting the accumulation of the substrates p27 and E-cadherin; Skp1 overexpression attenuated while Skp1 knockdown enhanced these effects of Bru in non-small cell lung cancer (NSCLC) cells. Moreover, Bru binding to Skp1 also inhibited the β-TRCP-SCF E3 ligase. In both subcutaneous and orthotopic NSCLC xenografts, Bru significantly inhibited the growth and metastasis of NSCLC through targeting SCF complex and upregulating p27 and E-cadherin protein levels. These data demonstrate that Bru is a Skp1-targeting agent that may have therapeutic potentials in lung cancer.
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Affiliation(s)
- Shangping Xing
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Feifei Nong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yaqin Wang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Da Huang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Jialiang Qin
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yu-Fei Chen
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Dan-Hua He
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Pei-En Wu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Huicai Huang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Ruoting Zhan
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Hui Xu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yong-Qiang Liu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
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Ye P, Chi X, Cha JH, Luo S, Yang G, Yan X, Yang WH. Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges. Cells 2021; 10:cells10123309. [PMID: 34943817 PMCID: PMC8699390 DOI: 10.3390/cells10123309] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.
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Affiliation(s)
- Peng Ye
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Xiaoxia Chi
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Jong-Ho Cha
- Department of Biomedical Science and Engineering, Graduate School, Inha University, Incheon 22212, Korea;
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea
| | - Shahang Luo
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Guanghui Yang
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Xiuwen Yan
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
- Correspondence: (X.Y.); (W.-H.Y.)
| | - Wen-Hao Yang
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan
- Correspondence: (X.Y.); (W.-H.Y.)
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He D, Chen Y, Zhou Y, Zhang S, Hong M, Yu X, Wei S, Fan X, Li S, Wang Q, Lu Y, Liu Y. Phytochemical library screening reveals betulinic acid as a novel Skp2-SCF E3 ligase inhibitor in non-small cell lung cancer. Cancer Sci 2021; 112:3218-3232. [PMID: 34080260 PMCID: PMC8353894 DOI: 10.1111/cas.15005] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/22/2021] [Accepted: 05/31/2021] [Indexed: 12/18/2022] Open
Abstract
Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome-dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant-derived Skp2 inhibitor, betulinic acid (BA), via high-throughput structure-based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non-small cell lung cancer (NSCLC) through targeting Skp2-SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H-bonds with residue Lys145, decreases its stability by disrupting Skp1-Skp2 interactions, thereby inhibiting the Skp2-SCF E3 ligase and promoting the accumulation of its substrates; that is, E-cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2-SCF E3 ligase and upregulating p27 and E-cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.
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Affiliation(s)
- Dan‐Hua He
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
- Research Center of Chinese Herbal Resources Science and EngineeringSchool of Pharmaceutical Sciences, Key Laboratory of Chinese Medicinal Resource from LingnanMinistry of EducationGuangzhou University of Chinese MedicineGuangzhouChina
| | - Yu‐Fei Chen
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
- Research Center of Chinese Herbal Resources Science and EngineeringSchool of Pharmaceutical Sciences, Key Laboratory of Chinese Medicinal Resource from LingnanMinistry of EducationGuangzhou University of Chinese MedicineGuangzhouChina
| | - Yi‐Le Zhou
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Shi‐Bing Zhang
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Ming Hong
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Xianjun Yu
- Laboratory of Inflammation and Molecular PharmacologySchool of Basic Medical Sciences and Biomedical Research InstituteHubei University of MedicineShiyanChina
| | - Su‐Fen Wei
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Xiang‐Zhen Fan
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Si‐Yi Li
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Qi Wang
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Yongzhi Lu
- Guangzhou Regenerative Medicine and Health Guangdong LaboratoryGuangzhouChina
- State Key Laboratory of Respiratory DiseaseGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina
| | - Yong‐Qiang Liu
- Institute of Clinical PharmacologyScience and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
- Research Center of Chinese Herbal Resources Science and EngineeringSchool of Pharmaceutical Sciences, Key Laboratory of Chinese Medicinal Resource from LingnanMinistry of EducationGuangzhou University of Chinese MedicineGuangzhouChina
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