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Yao K, Zhan XY, Feng M, Yang KF, Zhou MS, Jia H. Furin, ADAM, and γ-secretase: Core regulatory targets in the Notch pathway and the therapeutic potential for breast cancer. Neoplasia 2024; 57:101041. [PMID: 39208688 PMCID: PMC11399603 DOI: 10.1016/j.neo.2024.101041] [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: 07/22/2024] [Revised: 08/14/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
The activation of the Notch pathway promotes the occurrence and progression of breast cancer. The Notch signal plays different roles in different molecular subtypes of breast cancer. In estrogen receptor-positive (ER+) breast cancer, the Notch pathway regulates the activity of estrogen receptors. In human epidermal growth factor receptor 2-positive (HER2+) breast cancer, crosstalk between Notch and HER2 enhances HER2 signal expression. In triple-negative breast cancer (TNBC), Notch pathway activation is closely linked to tumor invasion and drug resistance. This article offers a comprehensive review of the structural domains, biological functions, and key targets of Notch with a specific focus on the roles of Furin protease, ADAM metalloprotease, and γ-secretase in breast cancer and their potential as therapeutic targets. We discuss the functions and mutual regulatory mechanisms of these proteinases in the Notch pathway as well as other potential targets in the Notch pathway, such as the glycosylation process and key transcription factors. This article also introduces new approaches in the treatment of breast cancer, with a special focus on the molecular characteristics and treatment response differences of different subtypes. We propose that the core regulatory molecules of the Notch pathway may become key targets for development of personalized treatment, which may significantly improve treatment outcomes and prognosis for patients with breast cancer.
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Affiliation(s)
- Kuo Yao
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, 110034, China.
| | - Xiang-Yi Zhan
- School of Traditional Chinese Medicine, Shenyang Medical College, No. 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, PR China.
| | - Mei Feng
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, 110034, China.
| | - Ke-Fan Yang
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, 110034, China.
| | - Ming-Sheng Zhou
- Shenyang Key Laboratory of Vascular Biology, No. 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, PR China; Science and Experimental Research Center of Shenyang Medical College, No. 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, PR China.
| | - Hui Jia
- Shenyang Key Laboratory of Vascular Biology, No. 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, PR China; School of Traditional Chinese Medicine, Shenyang Medical College, No. 146 Huanghe North Street, Yuhong District, Shenyang City 110034, Liaoning Province, PR China.
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2
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Romaniuk-Drapała A, Totoń E, Taube M, Idzik M, Rubiś B, Lisiak N. Breast Cancer Stem Cells and Tumor Heterogeneity: Characteristics and Therapeutic Strategies. Cancers (Basel) 2024; 16:2481. [PMID: 39001543 PMCID: PMC11240630 DOI: 10.3390/cancers16132481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/27/2024] [Accepted: 07/05/2024] [Indexed: 07/16/2024] Open
Abstract
Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both "normal" breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination.
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Affiliation(s)
- Aleksandra Romaniuk-Drapała
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Ewa Totoń
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Magdalena Taube
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Malgorzata Idzik
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Natalia Lisiak
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
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Mustafa M, Abbas K, Alam M, Ahmad W, Moinuddin, Usmani N, Siddiqui SA, Habib S. Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC). Mol Cell Biochem 2024; 479:895-913. [PMID: 37247161 DOI: 10.1007/s11010-023-04772-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/18/2023] [Indexed: 05/30/2023]
Abstract
Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor) distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.
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Affiliation(s)
- Mohd Mustafa
- Department of Biochemistry, J.N. Medical College, Aligarh Muslim University, Aligarh, 202002, India
| | - Kashif Abbas
- Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Mudassir Alam
- Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Waleem Ahmad
- Department of Medicine, J.N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Moinuddin
- Department of Biochemistry, J.N. Medical College, Aligarh Muslim University, Aligarh, 202002, India
| | - Nazura Usmani
- Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Shahid Ali Siddiqui
- Department of Radiotherapy, J.N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Safia Habib
- Department of Biochemistry, J.N. Medical College, Aligarh Muslim University, Aligarh, 202002, India.
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4
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Wang M, Yu F, Zhang Y, Li P. Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy. Front Immunol 2024; 15:1352484. [PMID: 38444855 PMCID: PMC10912471 DOI: 10.3389/fimmu.2024.1352484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 02/06/2024] [Indexed: 03/07/2024] Open
Abstract
Notch signaling pathway is a highly conserved system of cell-to-cell communication that participates in various biological processes, such as stem cell maintenance, cell fate decision, cell proliferation and death during homeostasis and development. Dysregulation of Notch signaling has been associated with many aspects of cancer biology, such as maintenance of cancer stem-like cells (CSCs), cancer cell metabolism, angiogenesis and tumor immunity. Particularly, Notch signaling can regulate antitumor or pro-tumor immune cells within the tumor microenvironment (TME). Currently, Notch signaling has drawn significant attention in the therapeutic development of cancer treatment. In this review, we focus on the role of Notch signaling pathway in remodeling tumor immune microenvironment. We describe the impact of Notch signaling on the efficacy of cancer immunotherapies. Furthermore, we summarize the results of relevant preclinical and clinical trials of Notch-targeted therapeutics and discuss the challenges in their clinical application in cancer therapy. An improved understanding of the involvement of Notch signaling in tumor immunity will open the door to new options in cancer immunotherapy treatment.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | | | | | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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Feng M, Santhanam RK, Xing H, Zhou M, Jia H. Inhibition of γ-secretase/Notch pathway as a potential therapy for reversing cancer drug resistance. Biochem Pharmacol 2024; 220:115991. [PMID: 38135129 DOI: 10.1016/j.bcp.2023.115991] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/30/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023]
Abstract
The mechanism of tumor drug resistance is complex and may involve stem cell maintenance, epithelial-mesenchymal transition, the activation of survival signaling pathways, transporter protein expression, and tumor microenvironment remodeling, all of which are linked to γ-secretase/Notch signaling. Increasing evidence has shown that the activation of the γ-secretase/Notch pathway is a key driver of cancer progression and drug resistance development and that γ-secretase inhibitors (GSIs) may be the most promising agents for reversing chemotherapy resistance of tumors by targeting the γ-secretase/Notch pathway. Here, we systematically summarize the roles in supporting γ-secretase/Notch activation-associated transformation of cancer cells into cancer stem cells, promotion of the EMT process, PI3K/Akt, MEK/ERK and NF-κB activation, enhancement of ABC transporter protein expression, and TME alteration in mediating tumor drug resistance. Subsequently, we analyze the mechanism of GSIs targeting the γ-secretase/Notch pathway to reverse tumor drug resistance and propose the outstanding advantages of GSIs in treating breast cancer drug resistance over other tumors. Finally, we emphasize that the development of GSIs for reversing tumor drug resistance is promising.
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Affiliation(s)
- Mei Feng
- Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China; Shenyang Key Laboratory of Vascular Biology, Shenyang 110034, China
| | - Ramesh Kumar Santhanam
- Faculty of Science and Marine Environment, University Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - Huan Xing
- Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China
| | - Mingsheng Zhou
- Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China; Shenyang Key Laboratory of Vascular Biology, Shenyang 110034, China.
| | - Hui Jia
- School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang 110034, China.
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Vigolo M, Urech C, Lamy S, Monticone G, Zabaleta J, Hossain F, Wyczechowska D, Del Valle L, O’Regan RM, Miele L, Lehal R, Majumder S. The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer. Cancers (Basel) 2023; 15:3957. [PMID: 37568775 PMCID: PMC10416998 DOI: 10.3390/cancers15153957] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/27/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND The efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined. METHODS CB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students' t-test. A one-way or two-way ANOVA followed by Tukey's post-analysis was performed to analyze the in vivo efficacy study results. THE RESULTS CB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone. CONCLUSION our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.
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Affiliation(s)
- Michele Vigolo
- Cellestia Biotech AG, 4057 Basel, Switzerland; (M.V.); (C.U.); (S.L.)
| | - Charlotte Urech
- Cellestia Biotech AG, 4057 Basel, Switzerland; (M.V.); (C.U.); (S.L.)
| | - Sebastien Lamy
- Cellestia Biotech AG, 4057 Basel, Switzerland; (M.V.); (C.U.); (S.L.)
| | - Giulia Monticone
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (G.M.); (F.H.); (L.M.)
| | - Jovanny Zabaleta
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA;
| | - Fokhrul Hossain
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (G.M.); (F.H.); (L.M.)
| | - Dorota Wyczechowska
- Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA;
| | - Luis Del Valle
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA;
| | - Ruth M. O’Regan
- Department of Medicine, University of Rochester, Rochester, NY 14642, USA;
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (G.M.); (F.H.); (L.M.)
| | - Rajwinder Lehal
- Cellestia Biotech AG, 4057 Basel, Switzerland; (M.V.); (C.U.); (S.L.)
| | - Samarpan Majumder
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (G.M.); (F.H.); (L.M.)
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Tian Y, Zhang P, Mou Y, Yang W, Zhang J, Li Q, Dou X. Silencing Notch4 promotes tumorigenesis and inhibits metastasis of triple-negative breast cancer via Nanog and Cdc42. Cell Death Discov 2023; 9:148. [PMID: 37149651 PMCID: PMC10164131 DOI: 10.1038/s41420-023-01450-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 05/08/2023] Open
Abstract
Elucidation of individual Notch protein biology in specific cancer is crucial to develop safe, effective, and tumor-selective Notch-targeting therapeutic reagents for clinical use [1]. Here, we explored the Notch4 function in triple-negative breast cancer (TNBC). We found that silencing Notch4 enhanced tumorigenic ability in TNBC cells via upregulating Nanog expression, a pluripotency factor of embryonic stem cells. Intriguingly, silencing Notch4 in TNBC cells suppressed metastasis via downregulating Cdc42 expression, a key molecular for cell polarity formation. Notably, downregulation of Cdc42 expression affected Vimentin distribution, but not Vimentin expression to inhibit EMT shift. Collectively, our results show that silencing Notch4 enhances tumorigenesis and inhibits metastasis in TNBC, indicating that targeting Notch4 may not be a potential strategy for drug discovery in TNBC.
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Affiliation(s)
- Yuan Tian
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
- Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Peipei Zhang
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
- Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Yajun Mou
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
- Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Wenxiu Yang
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Junhong Zhang
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Qing Li
- Department of Orthopedics, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China
| | - Xiaowei Dou
- Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China.
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Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells 2023; 12:cells12050720. [PMID: 36899854 PMCID: PMC10001180 DOI: 10.3390/cells12050720] [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: 01/09/2023] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.
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Guo M, Niu Y, Xie M, Liu X, Li X. Notch signaling, hypoxia, and cancer. Front Oncol 2023; 13:1078768. [PMID: 36798826 PMCID: PMC9927648 DOI: 10.3389/fonc.2023.1078768] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
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Affiliation(s)
- Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Niu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Min Xie
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China,*Correspondence: Xiaochen Li,
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10
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Herbal Ingredients in the Prevention of Breast Cancer: Comprehensive Review of Potential Molecular Targets and Role of Natural Products. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6044640. [PMID: 36017236 PMCID: PMC9398845 DOI: 10.1155/2022/6044640] [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: 04/13/2022] [Revised: 07/06/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022]
Abstract
Among various cancers, breast cancer is the most prevalent type in women throughout the world. Breast cancer treatment is challenging due to complex nature of the etiology of disease. Cell division cycle alterations are often encountered in a variety of cancer types including breast cancer. Common treatments include chemotherapy, surgery, radiotherapy, and hormonal therapy; however, adverse effects and multidrug resistance lead to complications and noncompliance. Accordingly, there is an increasing demand for natural products from medicinal plants and foods. This review summarizes molecular mechanisms of signaling pathways in breast cancer and identifies mechanisms by which natural compounds may exert their efficacy in the treatment of breast cancer.
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11
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Pongjantarasatian S, Nowwarote N, Rotchanakitamnuai V, Srirodjanakul W, Saehun R, Janebodin K, Manokawinchoke J, Fournier BPJ, Osathanon T. A γ-Secretase Inhibitor Attenuates Cell Cycle Progression and Invasion in Human Oral Squamous Cell Carcinoma: An In Vitro Study. Int J Mol Sci 2022; 23:8869. [PMID: 36012128 PMCID: PMC9408752 DOI: 10.3390/ijms23168869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/06/2022] [Accepted: 08/08/2022] [Indexed: 12/13/2022] Open
Abstract
Notch signaling is associated with many human malignancies, including oral squamous cell carcinoma (OSCC). However, the exact function of Notch signaling in OSCC remains unclear. Here, we investigated the effect of Notch signaling inhibition using a γ-secretase inhibitor (DAPT) on OSCC behaviours in vitro. Bioinformatic analysis of public-available gene expression profiles revealed the dysregulation of the Notch signaling pathway in OSCC compared with normal tissues, indicating the role of Notch signaling in OSCC regulation. RNA sequencing analysis of DAPT-treated human OSCC cells revealed the dysregulation of genes related to cell cycle-related pathways. Blocking Notch signaling significantly inhibited cell proliferation. DAPT-induced G0/G1 cell cycle arrest induced cell apoptosis. Furthermore, cell migration and invasion were also reduced in DAPT-treated cells. These findings indicate that Notch signaling activation participates in OSCC regulation by promoting cell growth, cell cycle progression, cell migration, and invasion. These mechanisms could facilitate OSCC progression. These results imply the potential use of Notch signaling inhibitors as a candidate adjuvant treatment in OSCC patients.
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Affiliation(s)
- Sarai Pongjantarasatian
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nunthawan Nowwarote
- Department of Oral Biology, Faculty of Dentistry, Universite Paris Cite, 75006 Paris, France
- Centre de Recherche des Cordeliers, INSERM UMRS 1138, Molecular Oral Pathophysiology, Universite Paris Cite, Sorbonne Universite, 75006 Paris, France
| | - Varumporn Rotchanakitamnuai
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Watcharee Srirodjanakul
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Ritmongkol Saehun
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kajohnkiart Janebodin
- Department of Anatomy, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand
| | - Jeeranan Manokawinchoke
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Benjamin P. J. Fournier
- Department of Oral Biology, Faculty of Dentistry, Universite Paris Cite, 75006 Paris, France
- Centre de Recherche des Cordeliers, INSERM UMRS 1138, Molecular Oral Pathophysiology, Universite Paris Cite, Sorbonne Universite, 75006 Paris, France
| | - Thanaphum Osathanon
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
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12
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Chaudhuri A, Kumar DN, Dehari D, Singh S, Kumar P, Bolla PK, Kumar D, Agrawal AK. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC). Pharmaceuticals (Basel) 2022; 15:542. [PMID: 35631368 PMCID: PMC9143332 DOI: 10.3390/ph15050542] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is considered one of the un-manageable types of breast cancer, involving devoid of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER 2) receptors. Due to their ability of recurrence and metastasis, the management of TNBC remains a mainstay challenge, despite the advancements in cancer therapies. Conventional chemotherapy remains the only treatment regimen against TNBC and suffers several limitations such as low bioavailability, systemic toxicity, less targetability, and multi-drug resistance. Although various targeted therapies have been introduced to manage the hardship of TNBC, they still experience certain limitations associated with the survival benefits. The current research thus aimed at developing and improving the strategies for effective therapy against TNBC. Such strategies involved the emergence of nanoparticles. Nanoparticles are designated as nanocavalries, loaded with various agents (drugs, genes, etc.) to battle the progression and metastasis of TNBC along with overcoming the limitations experienced by conventional chemotherapy and targeted therapy. This article documents the treatment regimens of TNBC along with their efficacy towards different subtypes of TNBC, and the various nanotechnologies employed to increase the therapeutic outcome of FDA-approved drug regimens.
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Affiliation(s)
- Aiswarya Chaudhuri
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Deepa Dehari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Sanjay Singh
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
- Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India
| | - Pradeep Kumar
- Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa;
| | - Pradeep Kumar Bolla
- Department of Biomedical Engineering, College of Engineering, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX 79968, USA;
| | - Dinesh Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
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13
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 518] [Impact Index Per Article: 172.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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14
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Yang R, Li Y, Wang H, Qin T, Yin X, Ma X. Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy. MOLECULAR BIOMEDICINE 2022; 3:8. [PMID: 35243562 PMCID: PMC8894518 DOI: 10.1186/s43556-022-00071-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer, with estrogen receptor, human epidermal growth factor receptor 2 and progesterone receptor negative. TNBC is characterized by high heterogeneity, high rates of metastasis, poor prognosis, and lack of therapeutic targets. Now the treatment of TNBC is still based on surgery and chemotherapy, which is effective only in initial stage but almost useless in advanced stage. And due to the lack of hormone target, hormonal therapies have little beneficial effects. In recent years, signaling pathways and receptor-specific targets have been reported to be effective in TNBC patients under specific clinical conditions. Now targeted therapies have been approved for many other cancers and even other subtypes of breast cancer, but treatment options for TNBC are still limited. Most of TNBC patients showed no response, which may be related to the heterogeneity of TNBC, therefore more effective treatments and predictive biomarkers are needed. In the present review, we summarize potential treatment opinions for TNBC based on the dysregulated receptors and signaling pathways, which play a significant role in multiple stages of TNBC development. We also focus on the application of immunotherapy in TNBC, and summarize the preclinical and clinical trials of therapy for patients with TNBC. We hope to accelerate the research and development of new drugs for TNBC by understanding the relevant mechanisms, and to improve survival.
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Affiliation(s)
- Ruoning Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China.,Department of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yueyi Li
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Hang Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Taolin Qin
- West China Hospital, West China Medical School Sichuan University, Chengdu, PR, China
| | - Xiaomeng Yin
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China.
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15
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Anobile DP, Montenovo G, Pecoraro C, Franczak M, Ait Iddouch W, Peters GJ, Riganti C, Giovannetti E. Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma. Expert Rev Clin Pharmacol 2022; 15:305-322. [PMID: 35533249 DOI: 10.1080/17512433.2022.2074835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/04/2022] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Malignant mesothelioma (MMe) is an aggressive rare cancer of the mesothelium, associated with asbestos exposure. MMe is currently an incurable disease at all stages mainly due to resistance to treatments. It is therefore necessary to elucidate key mechanisms underlying chemoresistance, in an effort to exploit them as novel therapeutic targets. AREAS COVERED Chemoresistance is frequently elicited by microRNA (miRNA) alterations and splicing deregulations. Indeed, several miRNAs, such as miR-29c, have been shown to exert oncogenic or oncosuppressive activity. Alterations in the splicing machinery might also be involved in chemoresistance. Moreover, the Notch signaling pathway, often deregulated in MMe, plays a key role in cancer stem cells formation and self-renewal, leading to drug resistance and relapses. EXPERT OPINION The prognosis of MMe in patients varies among different tumors and patient characteristics, and novel biomarkers and therapies are warranted. This work aims at giving an overview of MMe, with a special focus on state-of-the-art treatments and new therapeutic strategies against vulnerabilities emerging from studies on epigenetics factors. Besides, this review is also the first to discuss the interplay between miRNAs and alternative splicing as well as the role of Notch as new promising frontiers to overcome drug resistance in MMe.
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Affiliation(s)
- Dario P Anobile
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Oncology, University of Torino, Orbassano, Italy
| | - Giulia Montenovo
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Pecoraro
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Farmaceutiche (STEBICEF), Università degli Studi di PalermoDipartimento Di Scienze E Tecnologie Biologiche Chimiche E , Palermo, Italy
| | - Marika Franczak
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Widad Ait Iddouch
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Chiara Riganti
- Department of Oncology, University of Torino, Orbassano, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Fondazione Pisana per la Scienza Pisa, 56100 Pisa, Italy
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Cravero K, Pantone MV, Shin DH, Bergman R, Cochran R, Chu D, Zabransky DJ, Karthikeyan S, Waters IG, Hunter N, Rosen DM, Kyker-Snowman K, Dalton WB, Button B, Shinn D, Wong HY, Donaldson J, Hurley PJ, Croessmann S, Park BH. NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model. Oncotarget 2022; 13:373-386. [PMID: 35186194 PMCID: PMC8849273 DOI: 10.18632/oncotarget.28200] [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: 12/15/2021] [Accepted: 02/07/2022] [Indexed: 12/01/2022] Open
Abstract
Activating variants in the PEST region of NOTCH1 have been associated with aggressive phenotypes in human cancers, including triple-negative breast cancer (TNBC). Previous studies suggested that PEST domain variants in TNBC patients resulted in increased cell proliferation, invasiveness, and decreased overall survival. In this study, we assess the phenotypic transformation of activating NOTCH1 variants and their response to standard of care therapies. AAV-mediated gene targeting was used to isogenically incorporate 3 NOTCH1 variants, including a novel TNBC frameshift variant, in two non-tumorigenic breast epithelial cell lines, MCF10A and hTERT-IMEC. Two different variants at the NOTCH1 A2241 site (A2441fs and A2441T) both demonstrated increased transformative properties when compared to a non-transformative PEST domain variant (S2523L). These phenotypic changes include proliferation, migration, anchorage-independent growth, and MAPK pathway activation. In contrast to previous studies, activating NOTCH1 variants did not display sensitivity to a gamma secretase inhibitor (GSI) or resistance to chemotherapies. This study demonstrates distinct transformative phenotypes are specific to a given variant within NOTCH1 and these phenotypes do not correlate with sensitivities or resistance to chemotherapies or GSIs. Although previous studies have suggested NOTCH1 variants may be prognostic for TNBC, our study does not demonstrate prognostic ability of these variants and suggests further characterization would be required for clinical applications.
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Affiliation(s)
- Karen Cravero
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- These authors contributed equally to this work
| | - Morgan V. Pantone
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Dong Ho Shin
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Riley Bergman
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Rory Cochran
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David Chu
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel J. Zabransky
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Swathi Karthikeyan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ian G. Waters
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Natasha Hunter
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D. Marc Rosen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kelly Kyker-Snowman
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - W. Brian Dalton
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Berry Button
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dan Shinn
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hong Yuen Wong
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Joshua Donaldson
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Paula J. Hurley
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Sarah Croessmann
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Ben Ho Park
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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17
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Small molecules targeting γ-secretase and their potential biological applications. Eur J Med Chem 2022; 232:114169. [DOI: 10.1016/j.ejmech.2022.114169] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/30/2022] [Accepted: 01/30/2022] [Indexed: 12/14/2022]
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18
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Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
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Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
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Damaskos C, Garmpis N, Garmpi A, Nikolettos K, Sarantis P, Georgakopoulou VE, Nonni A, Schizas D, Antoniou EA, Karamouzis MV, Nikolettos N, Kontzoglou K, Patsouras A, Voutyritsa E, Syllaios A, Koustas E, Trakas N, Dimitroulis D. Investigational Drug Treatments for Triple-Negative Breast Cancer. J Pers Med 2021; 11:652. [PMID: 34357119 PMCID: PMC8303312 DOI: 10.3390/jpm11070652] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/25/2021] [Accepted: 07/08/2021] [Indexed: 02/05/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) and accounts for 10-20% of cases. Due to the lack of expression of several receptors, hormone therapy is largely ineffective for treatment purposes. Nevertheless, TNBC often responds very well to chemotherapy, which constitutes the most often recommended treatment. New beneficial targeted therapies are important to be investigated in order to achieve enhanced outcomes in patients with TNBC. This review will focus on recent therapeutic innovations for TNBC, focusing on various inhibitors such as phosphoinositide 3-kinase (PI3K) pathway inhibitors, poly-ADP-ribosyl polymerase (PARP) inhibitors, aurora kinase inhibitors, histone deacetylase inhibitors (HDACIs), and immune checkpoint inhibitors.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Nikolaos Garmpis
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Nikolettos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | | | - Afroditi Nonni
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.S.)
| | - Efstathios A. Antoniou
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | - Nikos Nikolettos
- Obstetric-Gynecologic Clinic, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Konstantinos Kontzoglou
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Alexandros Patsouras
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Errika Voutyritsa
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Athanasios Syllaios
- First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.S.)
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | - Nikolaos Trakas
- Department of Biochemistry, Sismanogleio Hospital, 15126 Athens, Greece;
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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20
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Jia H, Wang Z, Zhang J, Feng F. γ-Secretase inhibitors for breast cancer and hepatocellular carcinoma: From mechanism to treatment. Life Sci 2021; 268:119007. [PMID: 33428878 DOI: 10.1016/j.lfs.2020.119007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 12/21/2022]
Abstract
The γ-secretase complex is a key hydrolase for many type 1 transmembrane proteins. It is very important for activation of the Notch receptor and regulation of target-gene transcription. Abnormal activation and expression of the Notch pathway are closely related to the occurrence and development of many tumor types, including breast cancer and liver cancer. In this review, we elaborated on the basic situation of γ-secretase complex and the biological function and role of γ-secretase in APP and Notch signal pathway are described in detail. Subsequently, all currently known γ-secretase inhibitors and γ-secretase modulators are listed and their mechanism of action, value of IC50, chemical structure and current research stage are summarized. Next, the selection presented the treatment progress of γ-secretase inhibitors in breast cancer and hepatocellular carcinoma in the past five years. Finally, the mechanism of action of γ-secretase-mediated breast cancer and hepatocellular carcinoma and the advantages and disadvantages of γ-secretase inhibitors are discussed, and the concept of further research is proposed.
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Affiliation(s)
- Hui Jia
- Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City 110840, Liaoning Province, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China
| | - Zuojun Wang
- Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City 110840, Liaoning Province, PR China
| | - Jingyi Zhang
- Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City 110840, Liaoning Province, PR China.
| | - Fan Feng
- Center for Clinical Laboratory, The Fifth Medical Center, General Hospital of Chinese PLA, Beijing 100039, PR China.
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21
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Tamiro F, Weng AP, Giambra V. Targeting Leukemia-Initiating Cells in Acute Lymphoblastic Leukemia. Cancer Res 2021; 81:4165-4173. [PMID: 33414170 DOI: 10.1158/0008-5472.can-20-2571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/02/2020] [Accepted: 01/04/2021] [Indexed: 11/16/2022]
Abstract
The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of self-renewing and giving rise to "differentiated" or non-LICs that make up the whole tumor. Cell populations enriched with LIC activity have been characterized in different hematopoietic malignancies, including human acute lymphoblastic leukemia (ALL). Related studies have also demonstrated that LICs are functionally distinct from bulk cells and modulated by distinct molecular signaling pathways and epigenetic mechanisms. Here we review several biological and clinical aspects related to LICs in ALL, including (i) immunophenotypic characterization of LIC-enriched subsets in human and mouse models of ALL, (ii) emerging therapeutics against regulatory signaling pathways involved in LIC progression and maintenance in T- and B-cell leukemias, (iii) novel epigenetic and age-related mechanisms of LIC propagation, and (iv) ongoing efforts in immunotherapy to eradicate LIC-enriched cell subsets in relapsed and refractory ALL cases. Current conventional treatments do not efficiently eliminate LICs. Therefore, innovative therapeutics that exclusively target LICs hold great promise for developing an effective cure for ALL.
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Affiliation(s)
- Francesco Tamiro
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Andrew P Weng
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Vincenzo Giambra
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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22
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Moore G, Annett S, McClements L, Robson T. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells 2020; 9:cells9061503. [PMID: 32575680 PMCID: PMC7349363 DOI: 10.3390/cells9061503] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022] Open
Abstract
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.
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Affiliation(s)
- Gillian Moore
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Lana McClements
- The School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
- Correspondence:
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