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Li Y, Liu F, Cai Q, Deng L, Ouyang Q, Zhang XHF, Zheng J. Invasion and metastasis in cancer: molecular insights and therapeutic targets. Signal Transduct Target Ther 2025; 10:57. [PMID: 39979279 PMCID: PMC11842613 DOI: 10.1038/s41392-025-02148-4] [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: 05/09/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.
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Affiliation(s)
- Yongxing Li
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China
| | - Fengshuo Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- McNair Medical Institute, Baylor College of Medicine, Houston, TX, USA
- Graduate School of Biomedical Science, Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, USA
| | - Qingjin Cai
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lijun Deng
- Department of Medicinal Chemistry, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- McNair Medical Institute, Baylor College of Medicine, Houston, TX, USA.
| | - Ji Zheng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China.
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Ahmadi Y, Faiq T, Abolhasani S. Impact of G1 phase kinetics on the acquisition of stemness in cancer cells: the critical role of cyclin D. Mol Biol Rep 2025; 52:230. [PMID: 39951181 DOI: 10.1007/s11033-025-10351-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 02/07/2025] [Indexed: 05/09/2025]
Abstract
Cancer stem cells (CSCs) represent a unique subpopulation of cells with the ability to self-renew and differentiate, thereby sustaining tumor growth and contributing to disease recurrence. Although CSCs predominantly reside in the G0 phase, their stem-like properties, such as the expression of specific CD markers, self-renewal, differentiation potential, tumor initiation, drug resistance, and increased invasive and metastatic potential, manifest during their active proliferative phase. Rapidly dividing cells exhibit alterations in their cell cycle, often characterized by shortened or bypassed G1 phases, a phenomenon observed in both embryonic stem cells and cancerous cells. Dysregulation of cell cycle control is a hallmark of cancer, leading to uncontrolled cellular proliferation and tumorigenesis. Disruption in key regulatory proteins, signaling pathways, and cell cycle checkpoints-particularly during the G1 phase-enables cancer cells to escape normal proliferation restrictions. The rapid cell-cycle progression can impair the timely degradation of proteins critical for cell cycle regulation, particularly cyclin D, thereby compromising proper cell cycle control. Therefore these proteins may be passed to daughter cells, promoting further rounds of rapid cycles. Additionally, cyclin D is often overexpressed in cancer cells, further exacerbating uncontrolled proliferation. These mechanisms may underpin key properties of CSCs, including rapid proliferation and their stem-like traits. This review examines the relationship between G1 phase kinetics and the acquisition of stem-like characteristics, emphasizing how rapid G1 phase progression and transitions between dormancy and active proliferation contribute to the emergence of CSC traits.
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Affiliation(s)
- Yasin Ahmadi
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaymaniyah, Kurdistan Region, Iraq.
| | - Tahran Faiq
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaymaniyah, Kurdistan Region, Iraq
| | - Sakhavat Abolhasani
- Department of Basic Sciences and Health, Sarab Faculty of Medical Sciences, Sarab, East Azerbaijan, Iran.
- Sarab School of Medical Sciences and Health Services, Sarab, East Azerbaijan, Iran.
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Rice CPJ, Chelakkot VS, Conohan NT, Hirasawa K. Cancer stem cell populations are resistant to 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT). Sci Rep 2025; 15:4367. [PMID: 39910203 PMCID: PMC11799205 DOI: 10.1038/s41598-025-88173-3] [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: 09/05/2024] [Accepted: 01/24/2025] [Indexed: 02/07/2025] Open
Abstract
Photodynamic therapy (PDT) is a minimally invasive treatment approved for many types of cancers. PDT involves the administration of photoactive substances called photosensitizers (PS) that selectively accumulate in cancer cells and are subsequently excited/activated by irradiation with light at wavelengths of optimal absorbance. Activated PS leads to the generation of singlet oxygen and other reactive oxygen species (ROS), promoting cancer cell death. 5-aminolevulinic acid (5-ALA) is a naturally occurring PS precursor, which is metabolically converted to the PS, protoporphyrin IX (PPIX). Although 5-ALA-PDT is effective at killing cancer cells, in prior studies conducted by our group we normally observed in in vitro experiments that approximately 5-10% of cells survive 5-ALA-PDT, which served as an impetus for further investigation. Identifying the mechanisms of resistance to 5-ALA-PDT-mediated cell death is important to prevent tumor recurrence following 5-ALA-PDT. Previously, we reported that oncogenic activation of Ras/MEK promotes PPIX efflux and reduces cellular sensitivity to 5-ALA-PDT through increased expression of ABCB1 transporter. As cancer stem cells (CSCs) are known to drive resistance to other cancer treatments and have high efflux of chemotherapeutic agents via ABC-family transporters, we hypothesize that CSCs underlie 5-ALA-PDT resistance. In this study, we determined (1) if CSCs are resistant to 5-ALA-PDT and (2) if CSCs play roles in establishing resistant populations of 5-ALA-PDT. When we compared CSC populations before and after 5-ALA-PDT, we found that CSCs were less susceptible to 5-ALA-PDT. Moreover, we found that the CSC population was enriched in 5-ALA-PDT-resistant cell lines compared to the parental cell line. Our results indicate that CSCs are not sensitive to 5-ALA-PDT, which may contribute to establishment of 5-ALA-PDT resistance.
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Affiliation(s)
- Chantel P J Rice
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Vipin Shankar Chelakkot
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Noah T Conohan
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Kensuke Hirasawa
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
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Pilotto Heming C, de Souza Barbosa I, Lyra Miranda R, Nogueira Ugarte O, Santório de São José V, Moura Neto V, Aran V. P-Glycoprotein Drives Glioblastoma Survival and Chemotherapy Resistance: Potential as a Promising Liquid Biopsy Biomarker. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(24)00476-0. [PMID: 39788485 DOI: 10.1016/j.ajpath.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/21/2024] [Accepted: 12/03/2024] [Indexed: 01/12/2025]
Abstract
Drug resistance is a major challenge in cancer therapy, and the expression of efflux pumps such as P-glycoprotein (P-gp, ABCB1) often correlates with poor prognosis in various tumors, including glioblastoma (GB). Considering that different roles for these proteins have been established in the biology of various tumors, this study aimed to investigate the functions of P-gp in GB-derived cells by evaluating its survival, migratory, and apoptosis-regulating capabilities, as well as its potential as a liquid biopsy biomarker. P-gp expression was diminished via siRNA to determine its exact role in GB biology. The P-gp mRNA levels were evaluated by using quantitative real-time RT-PCR. With respect to liquid biopsy, circulating cell-free RNA was extracted from plasma belonging to patients diagnosed with GB, and P-gp levels were compared with matching tumor tissues using digital PCR. P-gp silencing significantly decreased viability, increased apoptosis, and enhanced chemotherapy sensitivity in GB cells, although it did not affect migratory patterns. Finally, P-gp expression levels in circulating cell-free RNA from patients with GB matched tumor tissue, whereas healthy volunteers appeared to bear no circulating P-gp. Taken together, the results indicate that P-gp affects GB tumor biology beyond its known role in drug resistance and could integrate a broader molecular signature for future diagnosis via liquid biopsy.
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Affiliation(s)
- Carlos Pilotto Heming
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Isabel de Souza Barbosa
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Renan Lyra Miranda
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | | | | | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil; Post-Graduate Program in Anatomic Pathology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
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Díaz-Carballo D, Safoor A, Saka S, Noa-Bolaño A, D'Souza F, Klein J, Acikelli AH, Malak S, Rahner U, Turki AT, Höppner A, Kamitz A, Song W, Chen YG, Kamada L, Tannapfel A, Brinkmann S, Ochsenfarth C, Strumberg D. The neuroepithelial origin of ovarian carcinomas explained through an epithelial-mesenchymal-ectodermal transition enhanced by cisplatin. Sci Rep 2024; 14:29286. [PMID: 39592661 PMCID: PMC11599565 DOI: 10.1038/s41598-024-76984-9] [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: 04/09/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
Acquired resistance to platinum-derived cytostatics poses major challenges in ovarian carcinoma therapy. In this work, we show a shift in the epithelial-mesenchymal transition (EMT) process towards an "ectodermal" conversion of ovarian carcinoma cells in response to cisplatin treatment, a progression we have termed epithelial-mesenchymal-ectodermal transition (EMET). EMET appears to occur via the classical EMT as judged by a) the downregulation of several epithelial markers and b) upregulation of Vimentin, accompanied by various embryonal transcription factors and, importantly, a plethora of neuronal markers, consistent with ectodermal differentiation. Moreover, we isolated cells from ovarian carcinoma cultures exhibiting a dual neural/stemness signature and multidrug resistance (MDR) phenotype. We also found that the epithelial cells differentiate from these neural/stem populations, indicating that the cell of origin in this tumor must in fact be a neural cell type with stemness features. Notably, some transcription factors like PAX6 and PAX9 were not localized in the nucleoplasm of these cells, hinting at altered nuclear permeability. In addition, the neuronal morphology was rapidly established when commercially available and primary ovarian carcinoma cells were cultured in the form of organoids. Importantly, we also identified a cell type in regular ovarian tissues, which possess similar neural/stemness features as observed in 2D or 3D cultures. The signature of this cell type is amplified in ovarian carcinoma tumors, suggesting a neuroepithelial origin of this tumor type. In conclusion, we propose that ovarian carcinomas harbor a small population of cells with an intrinsic neuronal/stemness/MDR phenotype, serving as the cradle from which ovarian carcinoma evolves.
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Affiliation(s)
- David Díaz-Carballo
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany.
| | - Ayesha Safoor
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Sahitya Saka
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, USA
| | - Adrien Noa-Bolaño
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Flevy D'Souza
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Jacqueline Klein
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Ali H Acikelli
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Sascha Malak
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Udo Rahner
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Amin T Turki
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Anne Höppner
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Annabelle Kamitz
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Wanlu Song
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lalitha Kamada
- Clinic of Pediatric Oncology, Hematology and Immunology, Düsseldorf University Hospital , 40225, Düsseldorf, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany
| | - Sebastian Brinkmann
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany
| | - Crista Ochsenfarth
- Department of Anesthesia, Intensive Care, Pain and Palliative Medicine, Ruhr-University Bochum Medical School, Marien Hospital Herne, 44625, Herne, Germany
| | - Dirk Strumberg
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
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6
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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [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: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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Guo Y, Ashrafizadeh M, Tambuwala MM, Ren J, Orive G, Yu G. P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators. Drug Discov Today 2024; 29:104161. [PMID: 39245345 DOI: 10.1016/j.drudis.2024.104161] [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: 06/02/2024] [Revised: 08/07/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.
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Affiliation(s)
- Yang Guo
- Department of Respiratory and Critical Care Medicine, Shenyang Tenth People's Hospital (Shenyang Chest Hospital), No. 11 Beihai Street, Dadong District, Shenyang 110044, Liaoning, China
| | - Milad Ashrafizadeh
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
| | - Guiping Yu
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Nantong University, No. 163 Shoushan Road, Jiangyin, China.
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Patel D, Sethi N, Patel P, Shah S, Patel K. Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review. Eur J Pharm Biopharm 2024; 198:114267. [PMID: 38514020 DOI: 10.1016/j.ejpb.2024.114267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.
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Affiliation(s)
- Dhvani Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Nutan Sethi
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Paresh Patel
- Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Shreeraj Shah
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Kaushika Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India.
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Park M, Jung E, Park JM, Park S, Ko D, Seo J, Kim S, Nam KD, Kang YK, Farrand L, Hoang VH, Nguyen CT, La MT, Nam G, Park HJ, Ann J, Lee J, Kim YJ, Kim JY, Seo JH. The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer. Theranostics 2024; 14:2442-2463. [PMID: 38646654 PMCID: PMC11024854 DOI: 10.7150/thno.93236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/21/2024] [Indexed: 04/23/2024] Open
Abstract
Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.
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Affiliation(s)
- Minsu Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Eunsun Jung
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Jung Min Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Soeun Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Dongmi Ko
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Juyeon Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Seongjae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Kee Dal Nam
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Yong Koo Kang
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Lee Farrand
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia 5000, Australia
| | - Van-Hai Hoang
- Faculty of Pharmacy, PHENIKAA University, Hanoi 12116, Vietnam
| | - Cong-Truong Nguyen
- Department of Organic Chemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam
| | - Minh Thanh La
- Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Gibeom Nam
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Hyun-Ju Park
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Jihyae Ann
- Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeewoo Lee
- Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yoon-Jae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Ji Young Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Jae Hong Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea
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10
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Chandra J, Hasan N, Nasir N, Wahab S, Thanikachalam PV, Sahebkar A, Ahmad FJ, Kesharwani P. Nanotechnology-empowered strategies in treatment of skin cancer. ENVIRONMENTAL RESEARCH 2023; 235:116649. [PMID: 37451568 DOI: 10.1016/j.envres.2023.116649] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
In current scenario skin cancer is a serious condition that has a significant impact on world health. Skin cancer is divided into two categories: melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC). Because of its significant psychosocial effects and need for significant investment in new technology and therapies, skin cancer is an illness of global health relevance. From the patient's perspective chemotherapy considered to be the most acceptable form of treatment. However, significant negatives of chemotherapy such as severe toxicities and drug resistance pose serious challenges to the treatment. The field of nanomedicine holds significant promise for enhancing the specificity of targeting neoplastic cells through the facilitation of targeted drug delivery to tumour cells. The integration of multiple therapeutic modalities to selectively address cancer-promoting or cell-maintaining pathways constitutes a fundamental aspect of cancer treatment. The use of mono-therapy remains prevalent in the treatment of various types of cancer, it is widely acknowledged in the academic community that this conventional approach is generally considered to be less efficacious compared to the combination treatment strategy. The employment of combination therapy in cancer treatment has become increasingly widespread due to its ability to produce synergistic anticancer effects, mitigate toxicity associated with drugs, and inhibit multi-drug resistance by means of diverse mechanisms. Nanotechnology based combination therapy represents a promising avenue for the development of efficacious therapies for skin cancer within the context of this endeavour. The objective of this article is to provide a description of distinct challenges for efficient delivery of drugs via skin. This article also provides a summary of the various nanotechnology based combinatorial therapy available for skin cancer with their recent advances. This review also focuses on current status of clinical trials of such therapies.
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Affiliation(s)
- Jyoti Chandra
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nazeer Hasan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nazim Nasir
- Department of Basic Medical Sciences, College of Applied Medical Sciences, Khamis Mushait, Kingdom of Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 61421, Saudi Arabia
| | - Punniyakoti Veeraveedu Thanikachalam
- Department of Pharmaceutical Chemistry, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farhan Jalees Ahmad
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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11
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Gandhi VV, Gandhi KA, Goda JS, Kumbhare LB, Gota V, Kunwar A. Post-radiation treatment of 3,3'-diselenodipropionic acid augments cell kill by modulating DNA repair and cell migration pathways in A549 cells. IUBMB Life 2023; 75:811-829. [PMID: 37072689 DOI: 10.1002/iub.2727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/14/2023] [Indexed: 04/20/2023]
Abstract
Aim of the present study was to test whether ionizing radiation (IR) treatment along with 3,3'-diselenodipropionic acid (DSePA), a redox active organodiselenide achieved better tumor control by suppressing the growth and migration of lung cancer cells. The results indicated that post-IR (2 Gy) treatment of DSePA (5 μM) led to a significantly higher cell death as compared to that of DSePA and IR treatments separately. Importantly, combinatorial treatment also showed reduction in the proportion of cancer stem cells and the clonogenic survival of A549 cells. The mechanistic studies indicated that combinatorial treatment although exhibited reductive environment (marked by decrease in ROS and increase of GSH/GSSG) at early time points (2-6 h postradiation), slowed DNA repair, inhibited epithelial-mesenchymal transition (EMT)/cell migration and induced significant level of apoptosis. DSePA mediated suppression of ATM/DNAPKs/p53 (DNA damage response signaling) and Akt/G-CSF (EMT) pathways appeared to be the major mechanism responsible for its radio-modulating activity. Finally, the combined treatment of IR (2 Gy × 4) and DSePA (0.1-0.25 mg/kg body weight daily through oral gavage) showed a significantly higher tumor suppression of the A549 xenograft as compared to that of DSePA and IR treatments separately in the mouse model. In conclusion, post-IR treatment of DSePA augmented cell kill by inhibiting DNA repair and cell migration in A549 cells.
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Affiliation(s)
- Vishwa Vipulkumar Gandhi
- Homi Bhabha National Institute, Mumbai, Maharashtra, India
- Radiation and Photochemistry Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
| | - Khushboo Atulkumar Gandhi
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Jayant Sastri Goda
- Homi Bhabha National Institute, Mumbai, Maharashtra, India
- Department of Radiation Oncology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | | | - Vikram Gota
- Homi Bhabha National Institute, Mumbai, Maharashtra, India
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Amit Kunwar
- Homi Bhabha National Institute, Mumbai, Maharashtra, India
- Radiation and Photochemistry Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
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12
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Manogaran P, Anandan A, Vijaya Padma V. Isoliensinine augments the therapeutic potential of paclitaxel in multidrug-resistant colon cancer stem cells and induced mitochondria-mediated cell death. J Biochem Mol Toxicol 2023; 37:e23395. [PMID: 37424111 DOI: 10.1002/jbt.23395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 04/03/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023]
Abstract
Previously we have reported the isoliensinine (ISO) potentates the therapeutic potential of cisplatin in cisplatin resistant colorectal cancer stem cells. The present study evaluates the chemo-sensitizing potential of the combinatorial regimen of ISO and Paclitaxcel (PTX) on multidrug-resistant (MDR)-HCT-15 cells to reduce the dose requirement of both ISO and PTX. The results of the present study suggest that treatment with the combinatorial regimen of ISO and PTX enhanced the cytotoxic effect with resultant increase in apoptosis in MDR-HCT-15 cells as evident from the altered cellular morphology, G2/M cell cycle arrest, propidium iodide uptake, Annexin V, increased intracellular Ca2+ accumulation, decreased mitochondrial membrane potential, diminished ATP production, PARP-1 cleavage, altered expression of ERK1/2, and apoptotic proteins. Treatment with combinatorial regimen of ISO and PTX also modulated the expression of the transcription factors SOX2, OCT4 which determine the stemness of cancer cells. Thus, results of the present study suggest that ISO and PTX combination regimen induces apoptosis in MDR-HCT-15 in a synergistic manner.
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Affiliation(s)
- Prasath Manogaran
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Aparna Anandan
- Department of Biotechnology, Bharathiar University, Coimbatore, India
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13
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Sharma S, Choudhary S, Kaur S, Reddy MV, Thota N, Singh A, Koul S, Khan IA, Ahmed Z, Kumar A. Piperine analog PGP-41 treatment overcomes paclitaxel resistance in NCI/ADR-RES ovarian cells by inhibition of MDR1. Chem Biol Interact 2023:110569. [PMID: 37244399 DOI: 10.1016/j.cbi.2023.110569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023]
Abstract
Chemoresistance is one of the leading causes of the failure of chemotherapy. Overexpression of P-glycoprotein (P-gp) in cancer cells is one of the most important contributing factors toward the development of chemoresistance. This study was designed to synthesize the derivatives of dihydronaphthyl and to evaluate the P-gp inhibition activity of these compounds. Among all the compounds, PGP-41 showed the most potent P-gp inhibition activity in colorectal adenocarcinoma LS-180 cells. This compound showed potent P-gp inhibition activity in chemoresistant ovarian cell line NCI/ADR-RES. Paclitaxel is one of the first lines of drugs for treating ovarian cancer and is a substrate of P-gp; therefore, NCI/ADR-RES cells are highly resistant to treatment with paclitaxel. Based on this information, we evaluated PGP-41 to overcome the paclitaxel resistance of NCI/ADR-RES cells. PGP-41 was able to sensitize the NCI/ADR-RES cells to the treatment of paclitaxel, which was evident by the reduced IC50 value of paclitaxel from 6.64 μM to 0.12 μM. The sensitization of NCI/ADR-RES cells by PGP-41 was comparable to that of elacridar and Zosuquidar. Further studies revealed that the PGP-41 exerts its effect by downregulating the expression of P-gp. Reduction of P-gp activity leads to the accumulation of higher intracellular concentration of paclitaxel, and thus allowing it to interact with its targets, which further helps in its increased efficacy. Paclitaxel was able to arrest the sensitized NCI/ADR-RES cells into G2M phase, which ultimately led to the induction of apoptotic proteins and the death of cancer cells. Being a different scaffold from zosuquidar and elacridar, further studies are required to develop PGP-41 into a potential drug to overcome chemoresistance in cancer cells.
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Affiliation(s)
- Sadhana Sharma
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Academy of Scientific and Innovative Research, Ghaziabaad, 201002, India
| | - Sushil Choudhary
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Academy of Scientific and Innovative Research, Ghaziabaad, 201002, India
| | - Sukhleen Kaur
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Academy of Scientific and Innovative Research, Ghaziabaad, 201002, India
| | - M Venkat Reddy
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India
| | - Niranjan Thota
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Eurofins Selcia Ltd., Chelmsford, London, UK
| | - Amarinder Singh
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India
| | - Surrinder Koul
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India
| | - Inshad Ali Khan
- Department of Microbiology, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, 305817, India
| | - Zabeer Ahmed
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Academy of Scientific and Innovative Research, Ghaziabaad, 201002, India.
| | - Ajay Kumar
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180016, India; Academy of Scientific and Innovative Research, Ghaziabaad, 201002, India.
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14
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Kumar S, Sherman MY. Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us. Int J Mol Sci 2023; 24:ijms24087233. [PMID: 37108395 PMCID: PMC10138578 DOI: 10.3390/ijms24087233] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. In addition, we have demonstrated a major resistance mechanism associated with the elimination of hundreds of thousands of Top1 binding sites on DNA that can arise from the repair of prior Top1-dependent DNA cleavages. Here, we outline the major mechanisms of irinotecan resistance and highlight recent advancements in the field. We discuss the impact of resistance mechanisms on clinical outcomes and the potential strategies to overcome resistance to irinotecan. The elucidation of the underlying mechanisms of irinotecan resistance can provide valuable insights for the development of effective therapeutic strategies.
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Affiliation(s)
- Santosh Kumar
- Department of Molecular Biology, Ariel University, Ariel 40700, Israel
| | - Michael Y Sherman
- Department of Molecular Biology, Ariel University, Ariel 40700, Israel
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15
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Liu Z, Hayashi H, Matsumura K, Ogata Y, Sato H, Shiraishi Y, Uemura N, Miyata T, Higashi T, Nakagawa S, Mima K, Imai K, Baba H. Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer. Br J Cancer 2023; 128:844-856. [PMID: 36536047 PMCID: PMC9977781 DOI: 10.1038/s41416-022-02106-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.
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Affiliation(s)
- Zhao Liu
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
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16
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The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance. Int J Mol Sci 2022; 23:ijms232113577. [PMID: 36362359 PMCID: PMC9656305 DOI: 10.3390/ijms232113577] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure.
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17
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Pilotto Heming C, Muriithi W, Wanjiku Macharia L, Niemeyer Filho P, Moura-Neto V, Aran V. P-glycoprotein and cancer: what do we currently know? Heliyon 2022; 8:e11171. [PMID: 36325145 PMCID: PMC9618987 DOI: 10.1016/j.heliyon.2022.e11171] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer.
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18
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Ciszewski WM, Sobierajska K, Stasiak A, Wagner W. Lactate drives cellular DNA repair capacity: Role of lactate and related short-chain fatty acids in cervical cancer chemoresistance and viral infection. Front Cell Dev Biol 2022; 10:1012254. [PMID: 36340042 PMCID: PMC9627168 DOI: 10.3389/fcell.2022.1012254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/04/2022] [Indexed: 11/10/2023] Open
Abstract
The characteristic feature of a cancer microenvironment is the presence of a highly elevated concentration of L-lactate in the tumor niche. The lactate-rich environment is also maintained by commensal mucosal microbiota, which has immense potential for affecting cancer cells through its receptoric and epigenetic modes of action. Some of these lactate activities might be associated with the failure of anticancer therapy as a consequence of the drug resistance acquired by cancer cells. Upregulation of cellular DNA repair capacity and enhanced drug efflux are the most important cellular mechanisms that account for ineffective radiotherapy and drug-based therapies. Here, we present the recent scientific knowledge on the role of the HCA1 receptor for lactate and lactate intrinsic activity as an HDAC inhibitor in the development of an anticancer therapy-resistant tumor phenotype, with special focus on cervical cancer cells. In addition, a recent study highlighted the viable role of interactions between mammalian cells and microorganisms in the female reproductive tract and demonstrated an interesting mechanism regulating the efficacy of retroviral transduction through lactate-driven modulation of DNA-PKcs cellular localization. To date, very few studies have focused on the mechanisms of lactate-driven enhancement of DNA repair and upregulation of particular multidrug-resistance proteins in cancer cells with respect to their intracellular regulatory mechanisms triggered by lactate. This review presents the main achievements in the field of lactate impact on cell biology that may promote undesirable alterations in cancer physiology and mitigate retroviral infections.
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Affiliation(s)
| | | | - Anna Stasiak
- Department of Hormone Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Waldemar Wagner
- Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
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19
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Venkatas J, Daniels A, Singh M. The Potential of Curcumin-Capped Nanoparticle Synthesis in Cancer Therapy: A Green Synthesis Approach. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:3201. [PMID: 36144994 PMCID: PMC9502936 DOI: 10.3390/nano12183201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 06/16/2023]
Abstract
Cancer nanotherapeutics is an important field of research which utilizes nanomaterials as an approach to cancer therapy. Nano-mediated therapeutic delivery systems overcome the adverse side effects of traditional cancer treatment methods. Nanoparticles (NPs) are considered excellent tumor-targeting vehicles due to their compact and variable size, large surface area, ability to load several genes and drugs, and mediation of increased therapeutic payload uptake. Despite the rapid development of nanotechnology, there is growing concern regarding the possible long-term side effects of NPs on the environment and human health. Green chemistry using plant materials, such as curcumin, is a sustainable alternative to conventional reduction methods and confers dual reducing and capping properties. Curcumin is a bioactive compound isolated from the rhizome of the Curcuma longa plant, which exhibits various medicinal properties. Curcumin-capped NPs exhibit increased solubility, bioavailability, therapeutic indices, and antitumor properties. This review highlights the potential and antitumor properties of economical, simple, and eco-friendly curcumin-synthesized and capped NPs for the localized delivery of therapeutic genes and drugs to the cancer tumor microenvironment with fewer adverse side effects.
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20
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Zhang Y, Li C, Xia C, Wah To KK, Guo Z, Ren C, Wen L, Wang F, Fu L, Liao N. Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo. Cell Commun Signal 2022; 20:142. [PMID: 36104708 PMCID: PMC9472360 DOI: 10.1186/s12964-022-00955-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849.
Methods
The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses.
Results
MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations.
Conclusions
In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR.
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21
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A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis. Biomaterials 2022; 289:121781. [PMID: 36113331 DOI: 10.1016/j.biomaterials.2022.121781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/17/2022] [Accepted: 08/28/2022] [Indexed: 11/20/2022]
Abstract
Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.
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22
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Wu K, Zou L, Lei X, Yang X. Roles of ABCA1 in cancer (Review). Oncol Lett 2022; 24:349. [DOI: 10.3892/ol.2022.13469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/15/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Kun Wu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Longwei Zou
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoyong Lei
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
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Barreto IV, Pessoa FMCDP, Machado CB, Pantoja LDC, Ribeiro RM, Lopes GS, Amaral de Moraes ME, de Moraes Filho MO, de Souza LEB, Burbano RMR, Khayat AS, Moreira-Nunes CA. Leukemic Stem Cell: A Mini-Review on Clinical Perspectives. Front Oncol 2022; 12:931050. [PMID: 35814466 PMCID: PMC9270022 DOI: 10.3389/fonc.2022.931050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.
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Affiliation(s)
- Igor Valentim Barreto
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Flávia Melo Cunha de Pinho Pessoa
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Caio Bezerra Machado
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Laudreísa da Costa Pantoja
- Department of Pediatrics, Octávio Lobo Children’s Hospital, Belém, Brazil
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
| | | | | | - Maria Elisabete Amaral de Moraes
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Manoel Odorico de Moraes Filho
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | | | | | - André Salim Khayat
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
| | - Caroline Aquino Moreira-Nunes
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
- Ceará State University, Northeast Biotechnology Network (RENORBIO), Fortaleza, Brazil
- *Correspondence: Caroline Aquino Moreira-Nunes,
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Emran TB, Shahriar A, Mahmud AR, Rahman T, Abir MH, Siddiquee MFR, Ahmed H, Rahman N, Nainu F, Wahyudin E, Mitra S, Dhama K, Habiballah MM, Haque S, Islam A, Hassan MM. Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches. Front Oncol 2022; 12:891652. [PMID: 35814435 PMCID: PMC9262248 DOI: 10.3389/fonc.2022.891652] [Citation(s) in RCA: 233] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.
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Affiliation(s)
- Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Asif Shahriar
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, United States
| | - Aar Rafi Mahmud
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh
| | - Tanjilur Rahman
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Mehedy Hasan Abir
- Faculty of Food Science and Technology, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
| | | | - Hossain Ahmed
- Department of Biotechnology and Genetic Engineering, University of Development Alternative, Dhaka, Bangladesh
| | - Nova Rahman
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Dhaka, Bangladesh
| | - Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Elly Wahyudin
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Mahmoud M. Habiballah
- Medical Laboratory Technology Department, Jazan University, Jazan, Saudi Arabia
- SMIRES for Consultation in Specialized Medical Laboratories, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Bursa, Turkey
| | | | - Mohammad Mahmudul Hassan
- Queensland Alliance for One Health Sciences, School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
- Department of Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
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25
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Vaghari-Tabari M, Hassanpour P, Sadeghsoltani F, Malakoti F, Alemi F, Qujeq D, Asemi Z, Yousefi B. CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer. Cell Mol Biol Lett 2022; 27:49. [PMID: 35715750 PMCID: PMC9204876 DOI: 10.1186/s11658-022-00348-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 05/24/2022] [Indexed: 12/18/2022] Open
Abstract
The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. .,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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26
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Adhikari S, Bhattacharya A, Adhikary S, Singh V, Gadad S, Roy S, Das C. The paradigm of drug resistance in cancer: an epigenetic perspective. Biosci Rep 2022; 42:BSR20211812. [PMID: 35438143 PMCID: PMC9069444 DOI: 10.1042/bsr20211812] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.
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Affiliation(s)
- Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Apoorva Bhattacharya
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
| | - Santanu Adhikary
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Vipin Singh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Shrikanth S. Gadad
- Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A
- Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, U.S.A
| | - Siddhartha Roy
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
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27
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Cui Q, Liang XL, Wang JQ, Zhang JY, Chen ZS. Therapeutic implication of carbon monoxide in drug resistant cancers. Biochem Pharmacol 2022; 201:115061. [PMID: 35489394 DOI: 10.1016/j.bcp.2022.115061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 12/14/2022]
Abstract
Drug resistance is the major obstacle that undermines effective cancer treatment. Recently, the application of gas signaling molecules, e.g., carbon monoxide (CO), in overcoming drug resistance has gained significant attention. Growing evidence showed that CO could inhibit mitochondria respiratory effect and glycolysis, two major ATP production pathways in cancer cells, and suppress angiogenesis and inhibit the activity of cystathionine β-synthase that is important in regulating cancer cells homeostasis, leading to synergistic effects when combined with cisplatin, doxorubicin, or phototherapy, etc. in certain resistant cancer cells. In the current review, we attempted to have a summary of these research conducted in the past decade using CO in treating drug resistant cancers, and have a detailed interpretation of the underlying mechanisms. The critical challenges will be discussed and potential solutions will also be provided. The information collected in this work will hopefully evoke more effects in using CO for the treatment of drug resistant cancers.
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Affiliation(s)
- Qingbin Cui
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiao-Lan Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Jian-Ye Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA; Institute for Biotechnology, St. John's University, Queens, NY 11439, USA.
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28
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Sahabi K, Selvarajah GT, Mokrish A, Rasedee A, Kqueen CY. Development and molecular characterization of doxorubicin-resistant canine mammary gland tumour cells. JOURNAL OF APPLIED ANIMAL RESEARCH 2022. [DOI: 10.1080/09712119.2022.2032719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Kabiru Sahabi
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Gayathri T. Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Ajat Mokrish
- Department of Veterinary Preclinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Abdullah Rasedee
- Department of Veterinary Diagnostic Laboratory, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Cheah Y. Kqueen
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
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29
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Targeted liposomal doxorubicin/ceramides combinations: the importance to assess the nature of drug interaction beyond bulk tumor cells. Eur J Pharm Biopharm 2022; 172:61-77. [PMID: 35104605 DOI: 10.1016/j.ejpb.2022.01.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 12/26/2022]
Abstract
One of the major assets of anticancer nanomedicine is the ability to co-deliver drug combinations, as it enables targeting of different cellular populations and/or signaling pathways implicated in tumorigenesis and thus tackling tumor heterogeneity. Moreover, drug resistance can be circumvented, for example, upon co-encapsulation and delivery of doxorubicin and sphingolipids, as ceramides. Herein, the impact of short (C6) and long (C18) alkyl chain length ceramides on the nature of drug interaction, within the scope of combination with doxorubicin, was performed in bulk triple-negative breast cancer (TNBC) cells, as well as on the density of putative cancer stem cells and phenotype, including live single-cell tracking. C6- or C18-ceramide enabled a synergistic drug interaction in all conditions and (bulk) cell lines tested. However, differentiation among these two ceramides was reflected on the migratory potential of cancer cells, particularly significant against the highly motile MDA-MB-231 cells. This effect was supported by the downregulation of the PI3K/Akt pathway enabled by C6-ceramide and in contrast with C18-ceramide. The decrease of the migratory potential enabled by the targeted liposomal combinations is of high relevance in the context of TNBC, due to the underlying metastatic potential. Surprisingly, the nature of the drug interaction assessed at the level of bulk cancer cells revealed to be insufficient to predict whether a drug combination enables a decrease in the percentage of the master regulators of tumor relapse as ALDH+/high putative TNBC cancer stem cells, suggesting, for the first time, that it should be extended further down to this level.
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30
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Identification, Culture and Targeting of Cancer Stem Cells. Life (Basel) 2022; 12:life12020184. [PMID: 35207472 PMCID: PMC8879966 DOI: 10.3390/life12020184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.
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31
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Zahra MH, Nawara HM, Hassan G, Afify SM, Seno A, Seno M. Cancer Stem Cells Contribute to Drug Resistance in Multiple Different Ways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:125-139. [PMID: 36587305 DOI: 10.1007/978-3-031-12974-2_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many tumors are resistant to conventional cancer therapies because a tumor is composed of heterogeneous cell population. Especially, subpopulation of cancer stem cells, which have self-renewal and differentiation properties and responsible for the tumor initiation, is generally considered resistant to chemo-, radio-, and immune therapy. Understanding the mechanism of drug resistance in cancer stem cells should lead to establish more effective therapeutic strategies. Actually, different molecular mechanisms are conceivable for cancer stem cells acquiring drug resistance. These mechanisms include not only cytoplasmic signaling pathways but also the intercellular communications in the tumor microenvironment. Recently, a great deal of successful reports challenged to elucidate the mechanisms of drug resistance and to develop novel treatments targeting cancer stem cells.
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Affiliation(s)
- Maram H Zahra
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Hend M Nawara
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Ghmkin Hassan
- Department of Genomic Oncology and Oral Medicine, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Said M Afify
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia, Shebeen El-Kom, 32511, Egypt
| | - Akimasa Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan
| | - Masaharu Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan.
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Deregulation of the CD44-NANOG-MDR1 associated chemoresistance pathways of breast cancer stem cells potentiates the anti-cancer effect of Kaempferol in synergism with Verapamil. Toxicol Appl Pharmacol 2022; 437:115887. [DOI: 10.1016/j.taap.2022.115887] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 01/08/2023]
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33
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Rasouli A, Aliebrahimi S, Montazeri V, Ghahremani MH, Ostad SN. Combination effect of doxorubicin and HIF inhibitor on MCF-7 CD44+/CD24- subpopulation cells in hypoxic condition. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902020000318754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Affiliation(s)
| | | | | | | | - Seyed Nasser Ostad
- Tehran University of Medical Sciences, Iran; Tehran University of Medical Sciences, Iran
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Cao L, Zhu Y, Wang W, Wang G, Zhang S, Cheng H. Emerging Nano-Based Strategies Against Drug Resistance in Tumor Chemotherapy. Front Bioeng Biotechnol 2021; 9:798882. [PMID: 34950650 PMCID: PMC8688801 DOI: 10.3389/fbioe.2021.798882] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/19/2021] [Indexed: 02/05/2023] Open
Abstract
Drug resistance is the most significant causes of cancer chemotherapy failure. Various mechanisms of drug resistance include tumor heterogeneity, tumor microenvironment, changes at cellular levels, genetic factors, and other mechanisms. In recent years, more attention has been paid to tumor resistance mechanisms and countermeasures. Nanomedicine is an emerging treatment platform, focusing on alternative drug delivery and improved therapeutic effectiveness while reducing side effects on normal tissues. Here, we reviewed the principal forms of drug resistance and the new possibilities that nanomaterials offer for overcoming these therapeutic barriers. Novel nanomaterials based on tumor types are an excellent modality to equalize drug resistance that enables gain more rational and flexible drug selectivity for individual patient treatment. With the emergence of advanced designs and alternative drug delivery strategies with different nanomaterials, overcome of multidrug resistance shows promising and opens new horizons for cancer therapy. This review discussed different mechanisms of drug resistance and recent advances in nanotechnology-based therapeutic strategies to improve the sensitivity and effectiveness of chemotherapeutic drugs, aiming to show the advantages of nanomaterials in overcoming of drug resistance for tumor chemotherapy, which could accelerate the development of personalized medicine.
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Affiliation(s)
- Lei Cao
- Department of Pathology, Quanzhou Women’s and Children’s Hospital, Quanzhou, China
| | - Yuqin Zhu
- Department of Pathology, Quanzhou Women’s and Children’s Hospital, Quanzhou, China
| | - Weiju Wang
- Department of Pathology, Qingyuan Maternal and Child Health Hospital, Qingyuan, China
| | - Gaoxiong Wang
- Department of Pathology, Quanzhou Women’s and Children’s Hospital, Quanzhou, China
| | - Shuaishuai Zhang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Hongwei Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China
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Caspa Gokulan R, Devaraj H. Stem Cell Markers CXCR-4 and CD133 Predict Aggressive Phenotype and Their Double Positivity Indicates Poor Prognosis of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13235895. [PMID: 34885003 PMCID: PMC8656999 DOI: 10.3390/cancers13235895] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Oral cancer is one of the most frequent malignancies in the world, with a poor prognosis. The absence of accurate biomarkers for predicting oral cancer progression is the primary cause of treatment failures. Multiple studies have shown that cancer stem cells play a critical role in tumor growth and chemo resistance. We uncovered, for the first time, the importance of combinatorial expression of stem cell related molecules CXCR-4 and CD-133 as possible biomarkers to predict poor prognosis of oral squamous cell carcinoma. The findings will aid in the identification of high-risk cases in order to provide appropriate therapy. Abstract The activation of the SDF-1/CXCR-4 pathway is crucial for the invasion and metastasis of oral cancer cells. The CXCR-4 positive cells possess stem cell characteristics and express the cancer stem cell marker, CD133, in tumors of colon and pancreas. Despite several studies, the co-expression of CXCR-4 and CD133 and its significance is still largely unknown in oral cancer. Therefore, we aimed to investigate the impact of CXCR-4 and CD133 double positivity in the prognosis of oral cancer. The significance of PKC-δ, one of the key signaling molecules that regulates CXCR-4, was also analyzed. Immunohistochemistry and double immunofluorescence was used to investigate the co-localization of CXCR-4, PKC-δ and CD133 in the human tissues and cell lines of oral squamous cell carcinoma. The expression of CXCR-4, PKC-δ and CD133 were found to be higher in poorly differentiated and lymph node metastasis-positive cases. Interestingly, CXCR-4 positive cells showed positive staining for PKC-δ and CD133 in oral cancer tissue and cell lines. Moreover, CXCR-4+/CD133+ and CXCR-4+/PKC-δ+ double positive cases have the worst survival. We discovered, for the first time, that patients with expression of both CXCR-4 and CD133 have a lower survival rate, and CXCR-4+/CD133+, as well as CXCR-4+/PKC-δ+ double positivity, can be utilized to predict poor prognosis. CXCR-4, PKC-δ and CD133 might regulate aggressiveness and invasion of oral cancer cells.
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Xuan X, Tian C, Zhao M, Sun Y, Huang C. Mesenchymal stem cells in cancer progression and anticancer therapeutic resistance. Cancer Cell Int 2021; 21:595. [PMID: 34736460 PMCID: PMC8570012 DOI: 10.1186/s12935-021-02300-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/26/2021] [Indexed: 12/26/2022] Open
Abstract
Increasing evidence indicates that the tumor microenvironment appears to play an increasingly important role in cancer progression and therapeutic resistance. Several types of cells within the tumor stroma had distinct impacts on cancer progression, either promoting or inhibiting cancer cell growth. Mesenchymal stem cells (MSCs) are a distinct type of cells that is linked to tumor development. MSCs are recognized for homing to tumor locations and promoting or inhibiting cancer cell proliferation, angiogenesis and metastasis. Moreover, emerging studies suggests that MSCs are also involved in therapeutic resistance. In this review, we analyzed the existing researches and elaborate on the functions of MSCs in cancer progression and anticancer therapeutic resistance, demonstrating that MSCs may be a viable cancer therapeutic target.
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Affiliation(s)
- Xiuyun Xuan
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Chunxia Tian
- Department of Cardiology, Hubei Provincial Hospital of TCM, Wuhan, 430022, Hubei, China
| | - Mengjie Zhao
- Department of Dermatology, Zhongnan Hospital, Wuhan University, Wuhan, 430022, Hubei, China.
| | - Yanhong Sun
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Karimi-Shahri M, Javid H, Sharbaf Mashhad A, Yazdani S, Hashemy SI. Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1307-1323. [PMID: 35096289 PMCID: PMC8769515 DOI: 10.22038/ijbms.2021.58227.12934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/09/2022]
Abstract
For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs' role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs. To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.
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Affiliation(s)
- Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Ilam Institute for Medical Sciences, Ilam, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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da Costa VR, Araldi RP, Vigerelli H, D’Ámelio F, Mendes TB, Gonzaga V, Policíquio B, Colozza-Gama GA, Valverde CW, Kerkis I. Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications. Cells 2021; 10:2617. [PMID: 34685596 PMCID: PMC8533895 DOI: 10.3390/cells10102617] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.
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Affiliation(s)
- Vitor Rodrigues da Costa
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Rodrigo Pinheiro Araldi
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Hugo Vigerelli
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Fernanda D’Ámelio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Thais Biude Mendes
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Vivian Gonzaga
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Bruna Policíquio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Gabriel Avelar Colozza-Gama
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | | | - Irina Kerkis
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
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Evaluation of breast cancer stem cells in human primary breast carcinoma and their role in aggressive behavior of the disease. J Clin Transl Res 2021; 7:687-700. [PMID: 34778599 PMCID: PMC8580523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/07/2021] [Accepted: 09/07/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND AND AIM To delineate the underlying molecular mechanisms responsible for the intratumoral enrichment of breast cancer stem cells (BCSCs) in aggressive breast tumors, we evaluated the frequency and characteristics of BCSCs within the tumor tissue in primary human breast carcinomas. We assessed the expression profiles of various genes in cancer cells (CC) and stromal cells (SC) from these tumors to delineate the role played by the cellular niche in de novo origin or expansion of intra-tumoral cancer stem cells (CSC). METHOD The study included primary tumor and adjacent normal breast tissue specimens from chemotherapy-naïve breast carcinoma patients. The BCSCs, identified as Lin-CD44+CD24- and aldehyde dehydrogenase 1 A1 positive, were enumerated. The flow-cytometrically sorted stromal, and CC were processed for gene expression profiling using a custom-designed polymerase chain reaction array of genes known to facilitate disease progression. RESULTS The frequency of BCSCs within the tumor mass correlated significantly with histopathological and molecular grades of tumors, indicating a direct relationship of BCSC with the aggressive behavior of breast cancer. Further, a significantly increased expression of the genes associated with growth factors, cytokines and matricellular proteins in tumors were found in high BCSCs compared to Lo-BCSC tumors, suggesting the possible contribution of stromal and CC in an intratumoral expansion of CSCs. Similarly, a significant upregulation of genes associated with hypoxia and angiogenesis in Hi-BCSCs tumors further supported the role of a hypoxic environment. CONCLUSION Overall, the findings suggest the molecular crosstalk between SC and CC potentially (directly or indirectly) contributes to the expansion of CSC. RELEVANCE FOR PATIENTS The current study highlights the importance of CSC as a potential future predictive/prognostic marker for aggressive breast cancer. The present study predicts the potential risk stratification based on the frequency of BCSCs in primary breast tumors and existing prognostic factors.
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Kurokawa H, Matsui H. The Cytotoxicity of Doxorubicin Can Be Accelerated by a Combination of Hyperthermia and 5-Aminolevulinic Acid. Antioxidants (Basel) 2021; 10:antiox10101531. [PMID: 34679666 PMCID: PMC8532950 DOI: 10.3390/antiox10101531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 01/23/2023] Open
Abstract
Chemotherapy is cytotoxic to various cancer cells and as well as normal cells. Thus, treatments that demonstrate selective cytotoxicity for cancer cells are desired. The combination of chemotherapy and other cancer therapies can show synergic cytotoxicity, which may be a clue to the nature of the involved cancer cellar-specific damage. We previously reported a phenomenon whereby mitochondrial reactive oxygen species (mitROS) regulate the expression transporters involved in anticancer drug transport and mitROS production is increased by hyperthermia. Moreover, the uptake of 5-aminolevulinic acid (ALA) was enhanced by the increase in mitROS production. In this study, we investigated whether the combination of hyperthermia and ALA can enhance the cytotoxicity of doxorubicin. MitROS production and ALA-derived porphyrin accumulation by hyperthermia (HT) were increased in a murine breast cancer cell line. The expression of solute carrier 15A1 (SLC15A1) upregulated and an ATP-binding cassette subfamily G member 2 (ABCG2) downregulated by HT. Since SLC15A1 is an accumulating transporter for ALA, while ABCG2 is a porphyrin efflux transporter, porphyrin accumulation was enhanced. ABCG2 is also a doxorubicin efflux transporter. Thus, ALA treatment accelerates the intracellular concentration of porphyrin, which acts as a competitive inhibitor of doxorubicin. Indeed, the amount of intracellular doxorubicin was increased by a combination of HT and ALA. The cytotoxicity of doxorubicin was also enhanced. This enhancement was observed in the human breast cancer cell line while it was not seen in normal cells. The combination of HT and ALA treatment can enhance the cancer-specific cytotoxicity of doxorubicin.
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Affiliation(s)
- Hiromi Kurokawa
- Algae Biomass Research and Development, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan;
- Correspondence: ; Tel.: +81-29-853-3466
| | - Hirofumi Matsui
- Algae Biomass Research and Development, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan;
- Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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Tan T, Li J, Luo R, Wang R, Yin L, Liu M, Zeng Y, Zeng Z, Xie T. Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review. Molecules 2021; 26:5792. [PMID: 34641334 PMCID: PMC8510449 DOI: 10.3390/molecules26195792] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells' sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial-mesenchymal transition, and so on. In this paper, the mechanisms of elemene's reversal of drug resistance are comprehensively reviewed.
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Affiliation(s)
- Tiantian Tan
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Jie Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ruhua Luo
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Rongrong Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Liyan Yin
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Mengmeng Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Yiying Zeng
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Zhaowu Zeng
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (T.T.); (J.L.); (R.L.); (R.W.); (L.Y.); (M.L.)
- Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China
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Tripathi D, Kulkarni S. Butein induces intrinsic pathway of apoptosis, vimentin proteolysis, and inhibition of cancer stem cell population in a human papillary thyroid cancer cell line. Toxicol In Vitro 2021; 77:105244. [PMID: 34481015 DOI: 10.1016/j.tiv.2021.105244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/16/2023]
Abstract
Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play an essential role in metastasis of papillary thyroid cancer (PTC). Further mesenchymal marker vimentin is linked with metastasis and cancer stem cell generation. Hence, inhibition of EMT and effective elimination of CSCs offers a novel target for the development of new therapeutic agents. The present study observed that at lower concentration, butein, a major bioactive chalcone, significantly inhibits NPA (papillary thyroid cancer cell line) cell migration and reduces extracellular acidification rate (ECAR) an indicator of enhanced glycolysis, required for cell migration. Additionally, at lower concentrations, butein treatment also suppresses vimentin phosphorylation, an essential step in cell migration, proving its potential against cell migration. Phosphorylation of vimentin is crucial in the protection of vimentin from caspase-mediated proteolysis. Interestingly, butein activates caspase-3 for the apoptosis execution at higher concentration; hence, total levels of vimentin were investigated. Butein induces caspase-3 mediated proteolysis of vimentin. Vimentin and glycolysis are essential for maintaining CSCs; therefore, aldeflour assay and side population assay were performed to investigate the effect of butein on CSCs. Our data suggest butein mediates the reduction in CSCs population. Here we report a novel mechanism of butein mediated inhibition of NPA cells migration by suppressing vimentin phosphorylation and its subsequent proteolysis. Collectively our data suggest the potential of butein as an innovative anticancer therapeutic agent for PTC management.
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Affiliation(s)
- Devavrat Tripathi
- Radiation Medicine Centre, Bhabha Atomic Research Centre, c/o TMH Annexe, Parel, Mumbai, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Savita Kulkarni
- Radiation Medicine Centre, Bhabha Atomic Research Centre, c/o TMH Annexe, Parel, Mumbai, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
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Modulating cell differentiation in cancer models. Biochem Soc Trans 2021; 49:1803-1816. [PMID: 34436513 DOI: 10.1042/bst20210230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 11/17/2022]
Abstract
Cancer has been traditionally viewed as a disease characterised by excessive and uncontrolled proliferation, leading to the development of cytotoxic therapies against highly proliferating malignant cells. However, tumours frequently relapse due to the presence of slow-cycling cancer stem cells eluding chemo and radiotherapy. Since these malignant stem cells are largely undifferentiated, inducing their lineage commitment has been proposed as a potential intervention strategy to deplete tumours from their most resistant components. Pro-differentiation approaches have thus far yielded clinical success in the reversion of acute promyelocytic leukaemia (APL), and new developments are fast widening their therapeutic applicability to solid carcinomas. Recent advances in cancer differentiation discussed here highlight the potential and outstanding challenges of differentiation-based approaches.
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Zhang B, Chan SH, Liu XQ, Shi YY, Dong ZX, Shao XR, Zheng LY, Mai ZY, Fang TL, Deng LZ, Zhou DS, Chen SN, Li M, Zhang XD. Targeting hexokinase 2 increases the sensitivity of oxaliplatin by Twist1 in colorectal cancer. J Cell Mol Med 2021; 25:8836-8849. [PMID: 34378321 PMCID: PMC8435428 DOI: 10.1111/jcmm.16842] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/01/2021] [Accepted: 07/20/2021] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance‐related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi‐drug resistance and epithelial‐mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E‐cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3‐bromopyruvate (3‐bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin‐mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.
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Affiliation(s)
- Bo Zhang
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Sze-Hoi Chan
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xue-Qi Liu
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yuan-Yuan Shi
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhao-Xia Dong
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xin-Rong Shao
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li-Yuan Zheng
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhi-Ying Mai
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tian-Liang Fang
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li-Zhi Deng
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Di-Sheng Zhou
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shu-Na Chen
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Miao Li
- Department of Hematology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Xing-Ding Zhang
- Molecular Cancer Research Center, School of Medicine, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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45
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An Y, Yang R, Wang X, Han Y, Jia G, Hu C, Zhang Z, Liu D, Tang Q. Facile Assembly of Thermosensitive Liposomes for Active Targeting Imaging and Synergetic Chemo-/Magnetic Hyperthermia Therapy. Front Bioeng Biotechnol 2021; 9:691091. [PMID: 34422777 PMCID: PMC8371754 DOI: 10.3389/fbioe.2021.691091] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/01/2021] [Indexed: 12/26/2022] Open
Abstract
Cancer stem cells (CSCs) are thought to be responsible for the recurrence of liver cancer, highlighting the urgent need for the development of effective treatment regimens. In this study, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and thermosensitive magnetoliposomes (TMs) conjugated to anti-CD90 (CD90@17-AAG/TMs) were developed for temperature-responsive CD90-targeted synergetic chemo-/magnetic hyperthermia therapy and simultaneous imaging in vivo. The targeting ability of CD90@DiR/TMs was studied with near-infrared (NIR) resonance imaging and magnetic resonance imaging (MRI), and the antitumor effect of CD90@17-AAG/TM-mediated magnetic thermotherapy was evaluated in vivo. After treatment, the tumors were analyzed with Western blotting, hematoxylin and eosin staining, and immunohistochemical (IHC) staining. The relative intensity of fluorescence was approximately twofold higher in the targeted group than in the non-targeted group, while the T 2 relaxation time was significantly lower in the targeted group than in the non-targeted group. The combined treatment of chemotherapy, thermotherapy, and targeting therapy exhibited the most significant antitumor effect as compared to any of the treatments alone. The anti-CD90 monoclonal antibody (mAb)-targeted delivery system, CD90@17-AAG/TMs, exhibited powerful targeting and antitumor efficacies against CD90+ liver cancer stem cells in vivo.
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Affiliation(s)
- Yanli An
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Rui Yang
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Xihui Wang
- School of Medicine, Southeast University, Nanjing, China
| | - Yong Han
- School of Medicine, Southeast University, Nanjing, China
| | - Gang Jia
- School of Medicine, Southeast University, Nanjing, China
| | - Chunmei Hu
- Department of Tuberculosis, The Second Affiliated Hospital of Southeast University (The Second Hospital of Nanjing), Nanjing, China
| | - Zhiyuan Zhang
- Department of Neurosurgery, Nanjing Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Dongfang Liu
- School of Medicine, Southeast University, Nanjing, China
| | - Qiusha Tang
- School of Medicine, Southeast University, Nanjing, China
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Eiro N, Fraile M, Fernández-Francos S, Sánchez R, Costa LA, Vizoso FJ. Importance of the origin of mesenchymal (stem) stromal cells in cancer biology: "alliance" or "war" in intercellular signals. Cell Biosci 2021; 11:109. [PMID: 34112253 PMCID: PMC8194017 DOI: 10.1186/s13578-021-00620-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.
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Affiliation(s)
- Noemi Eiro
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain.
| | - Maria Fraile
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Silvia Fernández-Francos
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Rosario Sánchez
- Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain
| | - Luis A Costa
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Francisco J Vizoso
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain. .,Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain.
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Keyvani-Ghamsari S, Khorsandi K, Rasul A, Zaman MK. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021; 13:120. [PMID: 34051847 PMCID: PMC8164819 DOI: 10.1186/s13148-021-01107-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
At present, after extensive studies in the field of cancer, cancer stem cells (CSCs) have been proposed as a major factor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell-like properties and tumorigenic capabilities, having the abilities of self-renewal and differentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti-tumor treatments. Highly resistant to conventional chemo- and radiotherapy, CSCs have heterogeneity and can migrate to different organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of different epigenetic pathways having effects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifications (DNA methylation, histone modifications, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can offer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors influencing the development thereof, with an emphasis on different types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer.
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Affiliation(s)
| | - Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran.
| | - Azhar Rasul
- Department of Zoology, Government College University Faisalabad, Faisalabad, 38000, Pakistan
| | - Muhammad Khatir Zaman
- Department of Biotechnology, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan
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Zhang Z, Xu Y, Zhao C. Fzd7/Wnt7b signaling contributes to stemness and chemoresistance in pancreatic cancer. Cancer Med 2021; 10:3332-3345. [PMID: 33934523 PMCID: PMC8124113 DOI: 10.1002/cam4.3819] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/27/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Mining databases and data obtained from assays on human specimens had shown that Fzd7 is closely associated with Wnt7b, that Fzd7/Wnt7b expression is upregulated in pancreatic cancer tissues compared with normal tissues, and its expression is negatively correlated with survival. Fzd7/Wnt7b knockdown in Capan‐2 and Panc‐1 cells reduced the proliferative capacity of pancreatic cancer stem cells (PCSCs), reduced drug resistance, decreased the percentage of CD24+CD44+ subset of cells and the levels of ABCG2, inhibited cell‐sphere formation, and reduced gemcitabine (GEM) resistance. In contrast, Fzd7/Wnt7b overexpression increased the percentage of the CD24+CD44+ subset of cells, and increased the levels of ABCG2 detected in cell spheroids. The gem‐resistant cells exhibited higher levels of Fzd7/Wnt7b expression, an increased percentage of CD24+CD44+ cells, and higher levels of ABCG2 compared with the parental cells. Taken together, Fzd7/Wnt7b knockdown can reduce PDAC cell stemness and chemoresistance by reducing the percentage of CSCs. Mechanistically, Fzd7 binds with Wnt7b and modulates the levels of β‐catenin, and they may exert their role via modulation of the canonical Wnt pathway.
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Affiliation(s)
- Zhongbo Zhang
- Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Yuanhong Xu
- Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Chenghai Zhao
- Department of Pathophysiology, Basic Medical College, China Medical University, Shenyang, P.R. China
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Penta D, Mondal P, Natesh J, Meeran SM. Dietary bioactive diindolylmethane enhances the therapeutic efficacy of centchroman in breast cancer cells by regulating ABCB1/P-gp efflux transporter. J Nutr Biochem 2021; 94:108749. [PMID: 33910062 DOI: 10.1016/j.jnutbio.2021.108749] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 01/13/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022]
Abstract
Overexpression of drug efflux transporters is commonly associated with multidrug-resistance in cancer therapy. Here for the first time, we investigated the ability of diindolylmethane (DIM), a dietary bioactive rich in cruciferous vegetables, in enhancing the efficacy of Centchroman (CC) by modulating the drug efflux transporters in human breast cancer cells. CC is a selective estrogen receptor modulator, having promising therapeutic efficacy against breast cancer. The combination of DIM and CC synergistically inhibited cell proliferation and induced apoptosis in breast cancer cells. This novel combination has also hindered the stemness of human breast cancer cells. Molecular docking analysis revealed that DIM had shown a strong binding affinity with the substrate-binding sites of ABCB1 (P-gp) and ABCC1 (MRP1) drug-efflux transporters. DIM has increased the intracellular accumulation of Hoechst and Calcein, the substrates of P-gp and MRP1, respectively, in breast cancer cells. Further, DIM stimulates P-gp ATPase activity, which indicates that DIM binds at the substrate-binding domain of P-gp, and thereby inhibits its efflux activity. Intriguingly, DIM enhanced the intracellular concentration of CC by inhibiting the P-gp and MRP1 expression as well as activity. The intracellular retaining of CC has increased its efficacy against breast cancer. Overall, DIM, a dietary bioactive, enhances the anticancer efficiency of CC through modulation of drug efflux ABC-transporters in breast cancer cells. Therefore, DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy against human breast cancer.
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Affiliation(s)
- Dhanamjai Penta
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jagadish Natesh
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line. Sci Rep 2021; 11:6556. [PMID: 33753859 PMCID: PMC7985213 DOI: 10.1038/s41598-021-86120-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 03/05/2021] [Indexed: 02/08/2023] Open
Abstract
Hyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.
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