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1
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Barnes DA, Janssen MJ, Yang H, Redegeld FA, Masereeuw R. An adverse outcome pathway for DNA adduct formation leading to kidney failure. Toxicology 2025; 515:154162. [PMID: 40268266 DOI: 10.1016/j.tox.2025.154162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/11/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
An Adverse Outcome Pathway (AOP) is a conceptual framework in toxicology and risk assessment that outlines the series of events from a chemical's molecular interaction to the resulting adverse health effect. This framework offers a structured approach to organizing biological knowledge, making it especially useful for understanding the mechanisms through which chemicals cause harm. Following a comprehensive analysis of the literature, an AOP was elucidated for key events linking DNA adduct formation, caused by compounds such as platinum anticancer drugs, to tubular necrosis, resulting in kidney failure. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The hydrolysis of platinum anticancer agents post-cellular uptake yields electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event. When DNA repair mechanisms become unbalanced, the nephrotoxic response following the formation of DNA adducts leads to DNA damage and mitochondrial dysfunction. These events promote the generation and release of reaction oxygen species (ROS) to induce oxidative stress, causing cell death and inflammation. Upon detachment from the basement membrane, these compromised cells are subsequently deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can lead to secondary toxicity and tubular necrosis, further exacerbating kidney injury and precipitating a progressive decline of renal function, finally resulting in kidney failure.
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Affiliation(s)
- D A Barnes
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - M J Janssen
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | | | - F A Redegeld
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - R Masereeuw
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
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2
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Pan C, Lee LTO. Membrane drug transporters in cancer: From chemoresistance mechanism to therapeutic strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189272. [PMID: 39863184 DOI: 10.1016/j.bbcan.2025.189272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/16/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
Chemoresistance is a multifactorial phenomenon and the primary cause to the ineffectiveness of oncotherapy and cancer recurrence. Membrane drug transporters are crucial for drug delivery and disposition in cancer cells. Changes in the expression and functionality of these transporters lead to decreased intracellular accumulation and reduced toxicity of antineoplastic drugs. As the mechanism has been better understood and genetic engineering technology progressed quickly in recent years, some novel targeting strategies have come to light. This article summarizes the regulatory mechanisms of membrane drug transporters and provides an extensive review of current approaches to address transporters-mediated chemoresistance. These strategies include the use of chemical inhibitors to block efflux transporters, the development of copper chelators to enhance platinum drug uptake, the delivery of genetic drugs to alter transporter expression, the regulation of transcription and post-translational modifications. Additionally, we provide information of the clinical trial performance of the related targeting strategies, along with the ongoing challenges. Even though some clinical trials failed due to unexpected side effects and limited therapeutic efficacy, the advent of targeting membrane drug transporters still presents a hopeful path for overcoming chemoresistance.
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Affiliation(s)
- Chao Pan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Leo Tsz On Lee
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China.
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3
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Jin SK, Baek KH. Unraveling the role of deubiquitinating enzymes on cisplatin resistance in several cancers. Biochim Biophys Acta Rev Cancer 2025; 1880:189297. [PMID: 40058507 DOI: 10.1016/j.bbcan.2025.189297] [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: 01/07/2025] [Revised: 03/03/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025]
Abstract
The use of platinum-based drugs in cancer treatment is one of the most common methods in chemotherapy. Especially, cisplatin induces cell death by interrupting DNA synthesis by binding to the DNA bases, thereby leading to the apoptosis via multiple pathways. However, the major hurdle in chemotherapy is drug resistance. To overcome drug resistance, the ubiquitin-proteasome system (UPS) has emerged as a potential therapeutic target. The UPS is a pivotal signaling pathway that regulates the majority of cellular proteins by attaching ubiquitin to substrates, leading to proteasomal degradation. Conversely, deubiquitinating enzymes (DUBs) remove tagged ubiquitin from the substrate and inhibit degradation, thereby maintaining proteostasis. Recently, studies have been conducted to identify the substrates of DUBs and investigated the cellular mechanisms, and now the development of therapeutics using DUB inhibitors is in clinical trials. However, the mechanism of the DUB response to cisplatin remains still unclear. In this review, we summarize the research reported on the function of DUBs responding to cisplatin.
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Affiliation(s)
- Sun-Kyu Jin
- Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea.
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Zou Q, Chen Y, Liu D, Du Q, Zhang C, Mai Q, Wang X, Lin X, Chen Q, Wei M, Chi C, Yao S, Liu J. Cuproptosis inhibits tumor progression and enhances cisplatin toxicity in ovarian cancer. FASEB J 2025; 39:e70484. [PMID: 40119652 PMCID: PMC11929041 DOI: 10.1096/fj.202500047r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/03/2025] [Accepted: 03/14/2025] [Indexed: 03/24/2025]
Abstract
Cuproptosis is a novel form of regulated cell death triggered by copper ion and copper ionophore. While cuproptosis has been actively explored as a potential target for cancer therapy, its role in ovarian cancer (OC) still remains unclear. In this study, we demonstrate that cuproptosis inhibits OC cell proliferation, migration, and invasion through FDX1 regulation and suppresses tumor growth in a mouse model. We also confirm that cuproptosis enhances OC sensitivity to cisplatin treatment both in vivo and in vitro. Moreover, our findings reveal that cuproptosis affects cholesterol biosynthesis in OC cells, with cholesterol playing a crucial role in its cytotoxic effect. Taken together, our results elucidate the effect of cuproptosis in OC and suggest it as a promising therapeutic strategy.
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Affiliation(s)
- Qiaojian Zou
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Yili Chen
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Duo Liu
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Qiqiao Du
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Chunyu Zhang
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Qiuwen Mai
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Xiaojun Wang
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Xiaoying Lin
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Qianrun Chen
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Mengxun Wei
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Chudan Chi
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Shuzhong Yao
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
| | - Junxiu Liu
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Obstetrics and GynecologyGuangdong Provincial Clinical Research Center for Obstetrical and Gynecological DiseasesGuangzhouChina
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Yao L, Jiang B, Xu D. Strategies to combat cancer drug resistance: focus on copper metabolism and cuproptosis. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:15. [PMID: 40201308 PMCID: PMC11977383 DOI: 10.20517/cdr.2025.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 04/10/2025]
Abstract
Cancer cells often develop tolerance to chemotherapy, targeted therapy, and immunotherapy drugs either before or during treatment. The significant heterogeneity among various tumors poses a critical challenge in modern cancer research, particularly in overcoming drug resistance. Copper, as an essential trace element in the body, participates in various biological processes of diseases, including cancers. The growth of many types of tumor cells exhibits a heightened dependence on copper. Thus, targeting copper metabolism or inducing cuproptosis may be potential ways to overcome cancer drug resistance. Copper chelators have shown potential in overcoming cancer drug resistance by targeting copper-dependent processes in cancer cells. In contrast, copper ionophores, copper-based nanomaterials, and other small molecules have been used to induce copper-dependent cell death (cuproptosis) in cancer cells, including drug-resistant tumor cells. This review summarizes the regulation of copper metabolism and cuproptosis in cancer cells and the role of copper metabolism and cuproptosis in cancer drug resistance, providing ideas for overcoming cancer resistance in the future.
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Affiliation(s)
- Leyi Yao
- Zhanjiang Institute of Clinical Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang 524033, Guangdong, China
- Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang 524033, Guangdong, China
- Authors contributed equally
| | - Baoyi Jiang
- Department of Orthopaedics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, Guangdong, China
- Authors contributed equally
| | - Dacai Xu
- Zhanjiang Institute of Clinical Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang 524033, Guangdong, China
- Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang 524033, Guangdong, China
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de Bakker T, Maes A, Dragan T, Martinive P, Penninckx S, Van Gestel D. Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer. Cells 2024; 14:18. [PMID: 39791719 PMCID: PMC11719474 DOI: 10.3390/cells14010018] [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: 11/19/2024] [Revised: 12/18/2024] [Accepted: 12/25/2024] [Indexed: 01/12/2025] Open
Abstract
Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario.
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Affiliation(s)
- Tycho de Bakker
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Anouk Maes
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Tatiana Dragan
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Philippe Martinive
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Sébastien Penninckx
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
- Medical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Dirk Van Gestel
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
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Miras I, Estévez-García P, Muñoz-Galván S. Clinical and molecular features of platinum resistance in ovarian cancer. Crit Rev Oncol Hematol 2024; 201:104434. [PMID: 38960218 DOI: 10.1016/j.critrevonc.2024.104434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024] Open
Abstract
Ovarian cancer is the most lethal of all the gynecological tumors despite remarkable advances in our understanding of its molecular biology. The cornerstone treatment remains cytoreductive surgery followed by platinum-based chemotherapy. Recently, the addition of targeted therapies, such as PARP inhibitors, as first-line maintenance has led to outstanding improvements, mainly in BRCA mutated and homologous recombination deficient tumors. However, a significant proportion of patients will experience recurrence, primarily due to platinum resistance, which ultimately result in fatality. Among these patients, primary platinum-resistant have a particularly dismal prognosis due to their low response to current available therapies, historical exclusion from clinical trials, and the absence of validated biomarkers. In this review, we discuss the concept of platinum resistance in ovarian cancer, the clinical and molecular characteristics of this resistance, and the current and new treatment options for these patients.
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Affiliation(s)
- Isabel Miras
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain; Medical Oncology Department. Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Purificación Estévez-García
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain; Medical Oncology Department. Hospital Universitario Virgen del Rocío, Seville, Spain; CIBER de CANCER, Institute of Health Carlos III, Madrid, Spain
| | - Sandra Muñoz-Galván
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain; CIBER de CANCER, Institute of Health Carlos III, Madrid, Spain.
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Marin JJG, Serrano MA, Herraez E, Lozano E, Ortiz-Rivero S, Perez-Silva L, Reviejo M, Briz O. Impact of genetic variants in the solute carrier ( SLC) genes encoding drug uptake transporters on the response to anticancer chemotherapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:27. [PMID: 39143954 PMCID: PMC11322974 DOI: 10.20517/cdr.2024.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/14/2024] [Accepted: 06/20/2024] [Indexed: 08/16/2024]
Abstract
Cancer drug resistance constitutes a severe limitation for the satisfactory outcome of these patients. This is a complex problem due to the co-existence in cancer cells of multiple and synergistic mechanisms of chemoresistance (MOC). These mechanisms are accounted for by the expression of a set of genes included in the so-called resistome, whose effectiveness often leads to a lack of response to pharmacological treatment. Additionally, genetic variants affecting these genes further increase the complexity of the question. This review focuses on a set of genes encoding members of the transportome involved in drug uptake, which have been classified into the MOC-1A subgroup of the resistome. These proteins belong to the solute carrier (SLC) superfamily. More precisely, we have considered here several members of families SLC2, SLC7, SLC19, SLC22, SLCO, SLC28, SLC29, SLC31, SLC46, and SLC47 due to the impact of their expression and genetic variants in anticancer drug uptake by tumor cells or, in some cases, general bioavailability. Changes in their expression levels and the appearance of genetic variants can contribute to the Darwinian selection of more resistant clones and, hence, to the development of a more malignant phenotype. Accordingly, to address this issue in future personalized medicine, it is necessary to characterize both changes in resistome genes that can affect their function. It is also essential to consider the time-dependent dimension of these features, as the genetic expression and the appearance of genetic variants can change during tumor progression and in response to treatment.
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Affiliation(s)
- Jose J. G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Maria A. Serrano
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Laura Perez-Silva
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
| | - Maria Reviejo
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid 28029, Spain
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Song HJ, Kim YH, Choi HN, Kim T, Kim SJ, Kang MW, Lee SD. TonEBP/NFAT5 expression is associated with cisplatin resistance and migration in macrophage-induced A549 cells. BMC Mol Cell Biol 2024; 25:6. [PMID: 38438872 PMCID: PMC10913585 DOI: 10.1186/s12860-024-00502-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 02/26/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Macrophages promote angiogenesis, metastasis, and drug resistance in several cancers. Similarly, TonEBP/NFAT5 induces metastasis in renal carcinoma and colon cancer cells. However, the role of this transcription factor and that of macrophages in lung cancer cells remains unclear. Therefore, this study investigated the effects of macrophages and TonEBP/NFAT5 expression on cisplatin resistance and migration in A549 lung adenocarcinoma cells. RESULTS A549 cells were cultured alone or indirectly co-cultured with THP-1-derived macrophages using a transwell culture chamber. Cisplatin-induced cell death was markedly decreased and migration increased in co-cultured A549 cells. Macrophage-conditioned media (CM) showed a similar effect on drug resistance and migration. Cisplatin-induced apoptosis, DNA fragmentation, and cleaved apoptotic proteins PARP and caspase-3 were markedly reduced in macrophage CM-induced A549 cells. Here, ERK, p38, JNK, and NF-κB activities were increased by macrophage CM. Furthermore, the proteins involved in cisplatin resistance and cancer cell migration were identified using specific inhibitors of each protein. ERK and NF-κB inhibition considerably reduced cisplatin resistance. The increase in macrophage CM-induced migration was partially reduced by treatment with ERK, JNK, and NF-κB inhibitors. TonEBP/NFAT5 expression was increased by macrophages, resulting in increased cisplatin resistance, cell migration, and invasion. Moreover, RNAi-mediated knockdown of TonEBP/NFAT5 reduced cisplatin resistance, migration, and invasion in macrophage CM-induced A549 cells. CONCLUSIONS These findings demonstrate that paracrine factors secreted from macrophages can change A549 cells, resulting in the induction of drug resistance against cisplatin and migration. In addition, the TonEBP/NFAT5 ratio, increased by macrophages, is an important regulator of the malignant transformation of cells.
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Affiliation(s)
- Hee Ju Song
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Young Hwan Kim
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Han Na Choi
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Taehee Kim
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Soo Jin Kim
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Min Woong Kang
- Department of thoracic surgery, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Sang Do Lee
- Department of Physiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
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10
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Fu R, Zhao B, Chen M, Fu X, Zhang Q, Cui Y, Hu X, Zhou W. Moving beyond cisplatin resistance: mechanisms, challenges, and prospects for overcoming recurrence in clinical cancer therapy. Med Oncol 2023; 41:9. [PMID: 38063931 DOI: 10.1007/s12032-023-02237-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/03/2023] [Indexed: 12/18/2023]
Abstract
Cisplatin, a classical platinum-based chemotherapy agent, has been a frontline treatment for various cancers for decades. However, its effectiveness has been hindered by the development of resistance, leading to cancer relapse. Addressing this challenge is crucial for both clinical practice and research. Hence, the imperative to unravel the intricate mechanisms underpinning cisplatin resistance and to uncover novel strategies to overcome this barrier holds immense significance. Within this review, we summarized the classification of platinum agents, highlighting their roles in therapeutic landscapes. We discussed the diverse mechanisms behind cisplatin resistance, including diminished intracellular cisplatin accumulation, intracellular detoxification, DNA repair, autophagy responses, heat shock proteins, tumor microenvironment, cancer stem cells, epigenetic regulation, ferroptosis resistance, and metabolic reprogramming. Drawing from this comprehensive understanding, we offered a series of prospective solutions to surmount cisplatin resistance and consequently mitigate the specter of disease recurrence within the realm of clinical cancer therapy.
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Affiliation(s)
- Rui Fu
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Borui Zhao
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Min Chen
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaolong Fu
- Department of Stomatology, Tianjin Haihe Hospital, Tianjin, 300222, China
| | - Qian Zhang
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Yange Cui
- Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Xin Hu
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China.
| | - Wei Zhou
- Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
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11
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Riisom M, Morrow SJ, Herbert CD, Tremlett WDJ, Astin JW, Jamieson SMF, Hartinger CG. In vitro and in vivo accumulation of the anticancer Ru complexes [Ru II(cym)(HQ)Cl] and [Ru II(cym)(PCA)Cl]Cl. J Biol Inorg Chem 2023; 28:767-775. [PMID: 37962611 DOI: 10.1007/s00775-023-02026-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 10/10/2023] [Indexed: 11/15/2023]
Abstract
The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [RuII(cym)(HQ)Cl] 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and [RuII(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.
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Affiliation(s)
- Mie Riisom
- School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Stuart J Morrow
- School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Caitlin D Herbert
- Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - William D J Tremlett
- School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Jonathan W Astin
- Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Stephen M F Jamieson
- Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Christian G Hartinger
- School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
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12
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Qi Y, Yao Q, Li X, Li X, Zhang W, Qu P. Cuproptosis-related gene SLC31A1: prognosis values and potential biological functions in cancer. Sci Rep 2023; 13:17790. [PMID: 37853210 PMCID: PMC10584849 DOI: 10.1038/s41598-023-44681-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023] Open
Abstract
Cuproptosis is a unique type of cell death that may influence tumour formation by targeting lipoylated tricarboxylic acid cycle proteins. Solute carrier family 31 member 1 (SLC31A1), an important copper transporter, influences dietary copper absorption in the cell membrane. However, various SLC31A1 properties in pan-cancer profiles remain unknown. This study investigated the role of SLC31A1 in human malignancies and analysed its prognostic value. Raw data were obtained from The Cancer Genome Atlas database and processed using numerous internet databases, including UALCAN, GEPIA, cBioPortal, TIMER2.0, and Human Protein Atlas. SLC31A1 expression was found to be elevated in cervical, endometrial, and breast cancers compared to that in normal tissues, but reduced in clear cell renal cell carcinoma, liver hepatocellular carcinoma, and lung adenocarcinoma. Furthermore, SLC31A1 expression was strongly associated with overall survival and disease-free survival in several cancers. SLC31A1 gene mutations and methylations were identified in 33 cancers. SLC31A1 expression was positively correlated with immune cells in immune infiltration data. Single-cell sequencing revealed that SLC31A1 may play key roles in DNA repair, DNA damage, and proliferation. These findings may lead to better understanding of SLC31A1 in pan-cancer profiles and suggest that SLC31A1 could be a viable predictive biomarker, particularly in gynaecological cancers.
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Affiliation(s)
- Yue Qi
- Clinical School of Obstetrics and Gynecology Center, Tianjin Medical University, Tianjin, China
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China
| | - Qingqing Yao
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xuanyan Li
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xinyu Li
- Clinical School of Obstetrics and Gynecology Center, Tianjin Medical University, Tianjin, China
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China
| | - Wenwen Zhang
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China.
| | - Pengpeng Qu
- Clinical School of Obstetrics and Gynecology Center, Tianjin Medical University, Tianjin, China.
- Department of Gynecological Oncology, Tianjin Central Hospital Gynecology Obstetrics, No. 156, Nansanma Road, Nankai District, Tianjin, 300000, China.
- Nankai University School of Medicine, Nankai University, Tianjin, China.
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13
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Zhang X, Shi X, Zhang D, Gong X, Wen Z, Demandel I, Zhang J, Rossello-Martinez A, Chan TJ, Mak M. Compression drives diverse transcriptomic and phenotypic adaptations in melanoma. Proc Natl Acad Sci U S A 2023; 120:e2220062120. [PMID: 37722033 PMCID: PMC10523457 DOI: 10.1073/pnas.2220062120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 08/07/2023] [Indexed: 09/20/2023] Open
Abstract
Physical forces are prominent during tumor progression. However, it is still unclear how they impact and drive the diverse phenotypes found in cancer. Here, we apply an integrative approach to investigate the impact of compression on melanoma cells. We apply bioinformatics to screen for the most significant compression-induced transcriptomic changes and investigate phenotypic responses. We show that compression-induced transcriptomic changes are associated with both improvement and worsening of patient prognoses. Phenotypically, volumetric compression inhibits cell proliferation and cell migration. It also induces organelle stress and intracellular oxidative stress and increases pigmentation in malignant melanoma cells and normal human melanocytes. Finally, cells that have undergone compression become more resistant to cisplatin treatment. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution.
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Affiliation(s)
- Xingjian Zhang
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
- Yale Cancer Center, Yale University, New Haven, CT06511
| | - Xin Shi
- School of Chemical Engineering and Technology, Tianjin University, Tianjin300350, China
| | - Dingyao Zhang
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
| | - Xiangyu Gong
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
| | - Zhang Wen
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
| | - Israel Demandel
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
| | - Junqi Zhang
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
| | | | - Trevor J. Chan
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - Michael Mak
- Department of Biomedical Engineering, Yale University, New Haven, CT06511
- Yale Cancer Center, Yale University, New Haven, CT06511
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Chang T, Lian Z, Ma S, Liang Z, Ma X, Wen X, Wang Y, Liu R. Combination with vorinostat enhances the antitumor activity of cisplatin in castration-resistant prostate cancer by inhibiting DNA damage repair pathway and detoxification of GSH. Prostate 2023; 83:470-486. [PMID: 36576015 DOI: 10.1002/pros.24479] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 11/25/2022] [Accepted: 12/02/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Like DNA methylation, histone modifications are considered important processes for epigenetic alterations in gene function, and abnormally high expression of histone deacetylases (HDACs) plays a key role in many human diseases. In addition to regulating the acetylation levels of histone and non-histone proteins and gene transcription, HDAC inhibitors as antitumor drugs can also affect the DNA damage repair (DDR) pathway in tumor cells. Prostate cancer (PCa) is one of the most heritable malignancies in which DDR pathway defects can be detected in a considerable proportion of cases. Such defects are more prevalent in castration-resistant prostate cancer (CRPC) and are highly enriched in metastatic lesions. There is currently evidence that DDR pathway-deficient PCa is associated with high-risk biological behaviors and response sensitivity to platinum-based chemotherapy. Platinum-based drugs have been used in multiple clinical trials as monotherapy or in combination with other chemotherapeutic agents for the treatment of CRPC. METHODS This study evaluated the combined anticancer effect of (cisplatin) CDDP and the HDAC inhibitors vorinostat (SAHA) on three androgen-dependent cell lines PC-3, DU-145, and C4-2B in vitro. The efficacy and safety of SAHA combined with CDDP in the treatment of CRPC were further verified through animal experiments. RESULTS The combination of the two drugs increases cytotoxic effects by increasing DNA damage. Our results showed that the SAHA could not only reduce the expression of homologous recombinant repair proteins BRCA2, BRCA1, PARP1, and RAD51, but also decrease enzymes that Reduce the key enzymes of GSH biosynthesis, GSS and GCLC, and GSTP1 which can catalyze the binding of GSH to cisplatin. The intracellular GSH level also decreased with the increase of SAHA concentration, at the same time, the content of intracellular Pt element. CONCLUSION The combination of CDDP and SAHA can produce synergistic anticancer effects in androgen-independent PCa cells in vitro and in vivo. Our results open up a new avenue for the effective treatment of CRPC. To optimize the chemotherapy regimen for patients with advanced PCa, it is necessary to further study the molecular mechanism of platinum drugs, HDAC inhibitors, and their combined action.
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Affiliation(s)
- Taihao Chang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhenpeng Lian
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Shenfei Ma
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhengxin Liang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xudong Ma
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xiaodong Wen
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yanming Wang
- Tianjin Key Laboratory of Molecular Drug Research, College of Pharmacy, Nankai University, Tianjin, China
| | - Ranlu Liu
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
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15
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Kong FS, Ren CY, Jia R, Zhou Y, Chen JH, Ma Y. Systematic pan-cancer analysis identifies SLC31A1 as a biomarker in multiple tumor types. BMC Med Genomics 2023; 16:61. [PMID: 36973786 PMCID: PMC10041742 DOI: 10.1186/s12920-023-01489-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 03/15/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Solute Carrier Family 31 Member 1 (SLC31A1) has recently been identified as a cuproptosis-regulatory gene. Recent studies have indicated that SLC31A1 may play a role in colorectal and lung cancer tumorigenesis. However, the role of SLC31A1 and its cuproptosis-regulatory functions in multiple tumor types remains to be further elucidated. METHODS Online websites and datasets such as HPA, TIMER2, GEPIA, OncoVar, and cProSite were used to extract data on SLC31A1 in multiple cancers. DAVID and BioGRID were used to conduct functional analysis and construct the protein-protein interaction (PPI) network, respectively. The protein expression data of SLC31A1 was obtained from the cProSite database. RESULTS The Cancer Genome Atlas (TCGA) datasets showed increased SLC31A1 expression in tumor tissues compared with non-tumor tissues in most tumor types. In patients with tumor types including adrenocortical carcinoma, low-grade glioma, or mesothelioma, higher SLC31A1 expression was associated with shorter overall survival and disease-free survival. S105Y was the most prevalent point mutation in SLC31A1 in TCGA pan-cancer datasets. Moreover, SLC31A1 expression was positively correlated with the infiltration of immune cells such as macrophages and neutrophils in tumor tissues in several tumor types. Functional enrichment analysis showed that SLC31A1 co-expressed genes were involved in protein binding, integral components of the membrane, metabolic pathways, protein processing, and endoplasmic reticulum. Copper Chaperone For Superoxide Dismutase, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha and Solute Carrier Family 31 Member 2 were copper homeostasis-regulated genes shown in the PPI network, and their expression was positively correlated with SLC31A1. Analysis showed there was a correlation between SLC31A1 protein and mRNA in various tumors. CONCLUSIONS These findings demonstrated that SLC31A1 is associated with multiple tumor types and disease prognosis. SLC31A1 may be a potential key biomarker and therapeutic target in cancers.
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Affiliation(s)
- Fan-Sheng Kong
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Chun-Yan Ren
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Ruofan Jia
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yuan Zhou
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology of Guangdong Academy of Science, Jiangnan University, Wuxi, Jiangsu, China.
- Jiangnan University Brain Institute, Wuxi, Jiangsu, China.
| | - Yaping Ma
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China.
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
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16
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Szefler B, Czeleń P. Will the Interactions of Some Platinum (II)-Based Drugs with B-Vitamins Reduce Their Therapeutic Effect in Cancer Patients? Comparison of Chemotherapeutic Agents such as Cisplatin, Carboplatin and Oxaliplatin-A Review. Int J Mol Sci 2023; 24:ijms24021548. [PMID: 36675064 PMCID: PMC9862491 DOI: 10.3390/ijms24021548] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Pt (II) derivatives show anti-cancer activity by interacting with nucleobases of DNA, thus causing some spontaneous and non-spontaneous reactions. As a result, mono- and diaqua products are formed which further undergo complexation with guanine or adenine. Consequently, many processes are triggered, which lead to the death of the cancer cell. The theoretical and experimental studies confirm that such types of interactions can also occur with other chemical compounds. The vitamins from B group have a similar structure to the nucleobases of DNA and have aromatic rings with single-pair orbitals. Theoretical and experimental studies were performed to describe the interactions of B vitamins with Pt (II) derivatives such as cisplatin, oxaliplatin and carboplatin. The obtained results were compared with the values for guanine. Two levels of simulations were implemented at the theoretical level, namely, B3LYP/6-31G(d,p) with LANL2DZ bases set for platinum atoms and MN15/def2-TZVP. The polarizable continuum model (IEF-PCM preparation) and water as a solvent were used. UV-Vis spectroscopy was used to describe the drug-nucleobase and drug-B vitamin interactions. Values of the free energy (ΔGr) show spontaneous reactions with mono- and diaqua derivatives of cisplatin and oxaliplatin; however, interactions with diaqua derivatives are more preferable. The strength of these interactions was also compared. Carboplatin products have the weakest interaction with the studied structures. The presence of non-covalent interactions was demonstrated in the tested complexes. A good agreement between theory and experiment was also demonstrated.
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17
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Zhang B, Zhang T, Zheng Z, Lin Z, Wang Q, Zheng D, Chen Z, Ma Y. Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma. Front Oncol 2023; 12:1020566. [PMID: 36713586 PMCID: PMC9877310 DOI: 10.3389/fonc.2022.1020566] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/22/2022] [Indexed: 01/14/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease. Therefore, more reliable biomarkers are required to better predict the prognosis of DLBCL. Cuproptosis is a novel identified form of programmed cell death (PCD) that is different from oxidative stress-related cell death (e.g., apoptosis, ferroptosis, and necroptosis) by Tsvetkov and colleagues in a recent study released in Science. Cuproptosis is copper-dependent PCD that is closely tied to mitochondrial metabolism. However, the prognostic value of cuproptosis-related genes (CRGs) in DLBCL remains to be further elucidated. In the present study, we systematically evaluated the molecular changes of CRGs in DLBCL and found them to be associated with prognosis. Subsequently, based on the expression profiles of CRGs, we characterized the heterogeneity of DLBCL by identifying two distinct subtypes using consensus clustering. Two isoforms exhibited different survival, biological functions, chemotherapeutic drug sensitivity, and immune microenvironment. After identifying differentially expressed genes (DEGs) between CRG clusters, we built a prognostic model with the Least absolute shrinkage and selection operator (LASSO) Cox regression analysis and validated its prognostic value by Cox regression analysis, Kaplan-Meier curves, and receiver operating characteristic (ROC) curves. In addition, the risk score can predict clinical characteristics, levels of immune cell infiltration, and prognosis. Furthermore, a nomogram incorporating clinical features and risk score was generated to optimize risk stratification and quantify risk assessment. Compared to the International Prognostic Index (IPI), the nomogram has demonstrated more accuracy in survival prediction. Furthermore, we validated the prognostic gene expression levels through external experiments. In conclusion, cuproptosis-related gene signature can serve as a potential prognostic predictor in DLBCL patients and may provide new insights into cancer therapeutic targets.
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Affiliation(s)
- Bingxin Zhang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tianyu Zhang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ziwei Zheng
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhili Lin
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Quanqiang Wang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dong Zheng
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zixing Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongyong Ma
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Yongyong Ma,
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Chen L, Chen L, Li X, Qin L, Zhu Y, Zhang Q, Tan D, He Y, Wang YH. Transcriptomic profiling of hepatic tissues for drug metabolism genes in nonalcoholic fatty liver disease: A study of human and animals. Front Endocrinol (Lausanne) 2023; 13:1034494. [PMID: 36686439 PMCID: PMC9845619 DOI: 10.3389/fendo.2022.1034494] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/08/2022] [Indexed: 01/05/2023] Open
Abstract
Background Drug metabolism genes are involved in the in vivo metabolic processing of drugs. In previous research, we found that a high-fat diet affected the transcript levels of mouse hepatic genes responsible for drug metabolism. Aims Our research intends to discover the drug metabolism genes that are dysregulated at the transcriptome level in nonalcoholic fatty liver disease (NAFLD). Methods We analyzed the transcriptome for drug metabolism genes of 35 human liver tissues obtained during laparoscopic cholecystectomy. Additionally, we imported transcriptome data from mice fed a high-fat diet in previous research and two open-access Gene Expression Omnibus (GEO) datasets (GSE63067 and GSE89632). Then, using quantitative real-time polymerase chain reaction (qRT-PCR), we cross-linked the differentially expressed genes (DEGs) in clinical and animal samples and validated the common genes. Results In this study, we identified 35 DEGs, of which 33 were up-regulated and two were down-regulated. Moreover, we found 71 DEGs (39 up- and 32 down-regulated), 276 DEGs (157 up- and 119 down-regulated), and 158 DEGs (117 up- and 41 down-regulated) in the GSE63067, GSE89632, and high-fat diet mice, respectively. Of the 35 DEGs, nine co-regulated DEGs were found in the Venn diagram (CYP20A1, CYP2U1, SLC9A6, SLC26A6, SLC31A1, SLC46A1, SLC46A3, SULT1B1, and UGT2A3). Conclusion Nine significant drug metabolism genes were identified in NAFLD. Future research should investigate the impacts of these genes on drug dose adjustment in patients with NAFLD. Clinical Trial Registration http://www.chictr.org.cn, identifier ChiCTR2100041714.
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Affiliation(s)
- Li Chen
- Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Lu Chen
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Xu Li
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Lin Qin
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yan Zhu
- Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qianru Zhang
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Daopeng Tan
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yuqi He
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yu-He Wang
- Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Key Laboratory of the Ministry of Education of the Basic Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, China
- The Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, China
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Qian X, Wang Y, Xie H, Wang C, Li J, Lei Y, Liu H, Wu Y, Li Y, Zhang Z. Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy. J Control Release 2023; 353:447-461. [PMID: 36470332 DOI: 10.1016/j.jconrel.2022.11.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/12/2022]
Abstract
The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO-) were largely produced, which could diffuse into regions over 400 μm away from the tumor vessels and be detectable after 24 h of radiation, thereby exhibiting superior efficacy in improving the spatiotemporal distribution in tumors versus common reactive oxygen species (ROS). Moreover, M-PFO mediated chemo-radiotherapy caused notable inhibition of tumor growth, with an 89.45% inhibition in HT-29 tumor models and a 92.69% suppression in CT-26 tumor models. Therefore, this bioinspired design provides an encouraging platform to improve intratumor spatiotemporal distribution to synergize chemo-radiotherapy.
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Affiliation(s)
- Xindi Qian
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuqi Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Honglei Xie
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
| | - Chen Wang
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Ying Lei
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai 201203, China
| | - Huanzhen Liu
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai 201203, China
| | - Yao Wu
- School of Pharmacy& Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai 201203, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Zhiwen Zhang
- School of Pharmacy& Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai 201203, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
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20
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Lim SY, Low ZE, Tan RPW, Lim ZC, Ang WH, Kubota T, Yamanaka M, Pang S, Simsek E, Li SFY. Single-cell and bulk ICP-MS investigation of accumulation patterns of Pt-based metallodrugs in cisplatin-sensitive and -resistant cell models. METALLOMICS : INTEGRATED BIOMETAL SCIENCE 2022; 14:6769858. [PMID: 36271844 DOI: 10.1093/mtomcs/mfac085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/15/2022] [Indexed: 12/14/2022]
Abstract
In research enabling preclinical development and attaining a deeper understanding of the behavior of metallodrugs in cancer cells with acquired resistance, intracellular Pt accumulation could be considered an important biomarker and analytical focus. In this work, Pt accumulation patterns in terms of the number of cells and Pt mass in single cells were precisely defined by using inductively coupled plasma-mass spectrometry (ICP-MS) operating in a fast time-resolved analysis mode. This technique is otherwise known as single-cell (SC)-ICP-MS. By applying the nascent and validated SC-ICP-MS technique, comparisons across three Pt drugs (cisplatin, carboplatin, and oxaliplatin) in the A2780 and A2780cis ovarian cancer cell models could be made. Additional roles of transporters on top of passive diffusion and the drugs' bioactivity could be postulated. The SC-ICP-MS-based observations also served as a cross-validation point to augment preexisting research findings on Pt-resistance mechanisms. Conjectures regarding S and Fe metabolism were also derived based on an additional and direct ICP-MS analysis of endogenous elements. Overall, our work not only confirms the utility of SC-ICP-MS in chemotherapeutic research, but also provided insights into further ICP-MS-based analytical capacities to be developed.
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Affiliation(s)
- Si Ying Lim
- NUS Graduate School's Integrative Sciences & Engineering Programme (ISEP), National University of Singapore, University Hall, Tan Chin Tuan Wing, Singapore 119077, Singapore
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Zhi En Low
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Regina Pei Woon Tan
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Zhi Chiaw Lim
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Wee Han Ang
- NUS Graduate School's Integrative Sciences & Engineering Programme (ISEP), National University of Singapore, University Hall, Tan Chin Tuan Wing, Singapore 119077, Singapore
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Tetsuo Kubota
- Agilent Technologies Japan Ltd., 9-1 Takakura-machi, Hachioji-shi, Tokyo 192-8510, Japan
| | - Michiko Yamanaka
- Agilent Technologies Japan Ltd., 9-1 Takakura-machi, Hachioji-shi, Tokyo 192-8510, Japan
| | - Steven Pang
- Agilent Technologies Singapore Pte. Ltd., Singapore768923, Singapore
| | - Erhan Simsek
- Agilent Technologies Singapore Pte. Ltd., Singapore768923, Singapore
| | - Sam Fong Yau Li
- NUS Graduate School's Integrative Sciences & Engineering Programme (ISEP), National University of Singapore, University Hall, Tan Chin Tuan Wing, Singapore 119077, Singapore
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
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21
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Forgie BN, Prakash R, Telleria CM. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int J Mol Sci 2022; 23:15410. [PMID: 36499737 PMCID: PMC9793759 DOI: 10.3390/ijms232315410] [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: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
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Affiliation(s)
- Benjamin N. Forgie
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Rewati Prakash
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Carlos M. Telleria
- Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
- Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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22
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Qiao H, Chen Z, Fu S, Yu X, Sun M, Zhai Y, Sun J. Emerging platinum(0) nanotherapeutics for efficient cancer therapy. J Control Release 2022; 352:276-287. [PMID: 36273531 DOI: 10.1016/j.jconrel.2022.10.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
Platinum (Pt)-based chemotherapy has been necessary for clinical cancer treatment. However, traditional bivalent drugs are hindered by poor physicochemical properties, severe toxic side effects, and drug resistance. Currently, elemental Pt(0) nanotherapeutics (NTs) have emerged to tackle the dilemma. The inherent acid-responsiveness of Pt(0) NTs could help to improve tumor selectivity and alleviate toxic effects. Moreover, the metal nature of Pt facilitates the great combination of Pt(0) NTs with photothermal and photodynamic therapy and imaging-guided diagnosis. Based on recent important researches, this review provides an updated introduction to Pt(0) NTs. First, the challenges of traditional Pt-based chemotherapy have been outlined. Then, Pt(0) NTs with multiple applications of tumor theranostics have been overviewed. Furthermore, the combinations of Pt(0) NTs with other therapeutical modalities are introduced. Last but not least, we envision the possible challenges and prospects associated with Pt(0) NTs.
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Affiliation(s)
- Han Qiao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Zhichao Chen
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China
| | - Shuwen Fu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Xiang Yu
- Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Affiliated Central Hospital Huzhou University, Huzhou, China
| | - Mengchi Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
| | - Yinglei Zhai
- School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
| | - Jin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
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23
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Abstract
Testicular cancer is a curable cancer. The success of physicians in curing the disease is underpinned by multidisciplinary advances. Cisplatin-based combination chemotherapy and the refinement of post-chemotherapy surgical procedures and diagnostic strategies have greatly improved long term survival in most patients. Despite such excellent outcomes, several controversial dilemmas exist in the approaches to clinical stage I disease, salvage chemotherapy, post-chemotherapy surgical procedures, and implementing innovative imaging studies. Relapse after salvage chemotherapy has a poor prognosis and the optimal treatment is not apparent. Recent research has provided insight into the molecular mechanisms underlying cisplatin resistance. Phase 2 studies with targeted agents have failed to show adequate efficacy; however, our understanding of cisplatin resistant disease is rapidly expanding. This review summarizes recent advances and discusses relevant issues in the biology and management of testicular cancer.
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Affiliation(s)
- Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, RI, USA
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24
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Schoeberl A, Gutmann M, Theiner S, Corte-Rodríguez M, Braun G, Vician P, Berger W, Koellensperger G. The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS. Front Mol Biosci 2022; 9:1055356. [PMID: 36518851 PMCID: PMC9742377 DOI: 10.3389/fmolb.2022.1055356] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/15/2022] [Indexed: 09/17/2023] Open
Abstract
More than a decade ago, studies on cellular cisplatin accumulation via active membrane transport established the role of the high affinity copper uptake protein 1 (CTR1) as a main uptake route besides passive diffusion. In this work, CTR1 expression, cisplatin accumulation and intracellular copper concentration was assessed for single cells revisiting the case of CTR1 in the context of acquired cisplatin resistance. The single-cell workflow designed for in vitro experiments enabled quantitative imaging at resolutions down to 1 µm by laser ablation-inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS). Cisplatin-sensitive ovarian carcinoma cells A2780 as compared to the cisplatin-resistant subline A2780cis were investigated. Intracellular cisplatin and copper levels were absolutely quantified for thousands of individual cells, while for CTR1, relative differences of total CTR1 versus plasma membrane-bound CTR1 were determined. A markedly decreased intracellular cisplatin concentration accompanied by reduced copper concentrations was observed for single A2780cis cells, along with a distinctly reduced (total) CTR1 level as compared to the parental cell model. Interestingly, a significantly different proportion of plasma membrane-bound versus total CTR1 in untreated A2780 as compared to A2780cis cells was observed. This proportion changed in both models upon cisplatin exposure. Statistical analysis revealed a significant correlation between total and plasma membrane-bound CTR1 expression and cisplatin accumulation at the single-cell level in both A2780 and A2780cis cells. Thus, our study recapitulates the crosstalk of copper homeostasis and cisplatin uptake, and also indicates a complex interplay between subcellular CTR1 localization and cellular cisplatin accumulation as a driver for acquired resistance development.
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Affiliation(s)
- Anna Schoeberl
- Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Michael Gutmann
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Sarah Theiner
- Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Mario Corte-Rodríguez
- Department of Physical and Analytical Chemistry, Faculty of Chemistry and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain
| | - Gabriel Braun
- Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Petra Vician
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Walter Berger
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Gunda Koellensperger
- Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
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25
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Pharmacokinetics of Carboplatin in Combination with Low-Dose Cyclophosphamide in Female Dogs with Mammary Carcinoma. Animals (Basel) 2022; 12:ani12223109. [PMID: 36428336 PMCID: PMC9686876 DOI: 10.3390/ani12223109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/12/2022] Open
Abstract
This prospective study aimed to evaluate the effect of metronomic cyclophosphamide on carboplatin’s tolerability, efficacy, and pharmacokinetics in dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were divided into groups: 300 mg/m2 intravenous (i.v.) carboplatin therapy (G1 = 8) or 300 mg/m2 i.v. carboplatin which was associated with 12.5 mg/m2 oral cyclophosphamide in a metronomic regimen (G2 = 8). The investigated animals underwent a clinical evaluation, a mastectomy, a carboplatin chemotherapy, and serial blood sampling for the pharmacokinetic analysis. The adverse events and survival rates were monitored. A non-compartmental analysis was applied to calculate the pharmacokinetic parameters of carboplatin in the 2nd and 4th chemotherapy cycles. Carboplatin PK showed high interindividual variability with a 10-fold variation in the area under the plasma concentration−time curve (AUC) in G1. The systemic plasma exposure to carboplatin was equivalent in both of the treatments considering the AUC and maximum plasma concentration (Cmax) values. Although the red blood cells (p < 0.0001), platelets (p = 0.0005), total leukocytes (p = 0.0002), and segmented neutrophils (p = 0.0007) were reduced in G2, the survival rate increased (p = 0.0044) when it was compared to G1. In conclusion, adding low daily doses of cyclophosphamide to a carboplatin therapy showed promising outcomes in female dogs with mammary tumors.
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26
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Buyana B, Naki T, Alven S, Aderibigbe BA. Nanoparticles Loaded with Platinum Drugs for Colorectal Cancer Therapy. Int J Mol Sci 2022; 23:11261. [PMID: 36232561 PMCID: PMC9569963 DOI: 10.3390/ijms231911261] [Citation(s) in RCA: 15] [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: 08/02/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is a common cancer in both men and women. Numerous studies on the therapeutic effectiveness of nanoparticles against colorectal cancer have been reported. Platinum treatments as well as other medications comprising of nanoparticles have been utilized. Drug resistance restricts the use of platinum medicines, despite their considerable efficacy against a variety of cancers. This review reports clinically licensed platinum medicines (cisplatin, carboplatin, and oxaliplatin) combined with various nanoparticles that have been evaluated for their therapeutic efficacy in the treatment of colorectal cancer, including their mechanism of action, resistance, and limitations.
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Affiliation(s)
| | | | | | - Blessing Atim Aderibigbe
- Department of Chemistry, University of Fort Hare, Alice 5700, Eastern Cape Province, South Africa
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27
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El-Shafai NM, Farrag F, Shukry M, Mehany H, Aboelmaati M, Abu-Ali O, Saleh D, Ramadan M, El-Mehasseb I. Effect of a Novel Hybrid Nanocomposite of Cisplatin-Chitosan on Induced Tissue Injury as a Suggested Drug by Reducing Cisplatin Side Effects. Biol Trace Elem Res 2022; 200:4017-4026. [PMID: 34719747 DOI: 10.1007/s12011-021-02994-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/26/2021] [Indexed: 10/19/2022]
Abstract
The self-assembly of cisplatin (Cis-Pt) and chitosan nanoparticles (Cs NPs) has been synthesized and characterized successfully by different analyses and techniques, such as scanning electron microscopy, ultraviolet-visible spectrophotometry, and Fourier transform infrared spectroscopy. The efficiency of loading Cis-Pt on Cs NPs for decreasing the side effects of Cis-Pt by loading it on Cs NP surface was revealed through histopathological and physiological measurements for the liver, testis, and kidney cells. Self-assembly hybrid nanocomposite (Cis-Pt@Cs) could improve spermatogenic cells, seminiferous tubules, and Leydig cells in the interstitial tissue. Kidney examination showed intact glomeruli with a mild increase in capsular space in addition to the intact renal tubular epithelial lining, and liver findings showed improvement in dilation and congestion of the central vein besides mild dilation of blood sinusoids in addition to a mild degree of hepatocyte vacuolation. The serum levels of hepatic, renal, and testicular marker analysis were measured, where Cis-Pt increased the serum levels of alanine aminotransferase, aspartate aminotransferase activity, urea, creatinine, and decreased testosterone levels, while synthesized self-assembly appeared normalized levels. From the results, the self-assembly hybrid nanocomposite decreases and improves the side effects of Cis-Pt.
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Affiliation(s)
- Nagi M El-Shafai
- Nanotechnology Center, Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafr El-Shaikh, 33516, Egypt.
| | - Foad Farrag
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Shaikh, Egypt
| | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Shaikh, Egypt
| | - Hany Mehany
- Nanotechnology Center, Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafr El-Shaikh, 33516, Egypt
| | - Mohamed Aboelmaati
- Institute of Nanoscience and Nanotechnology, KafrelSheikh University, Kafr El-Shaikh, Egypt
| | - Ola Abu-Ali
- Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Dalia Saleh
- Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Mohamed Ramadan
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Ibrahim El-Mehasseb
- Nanotechnology Center, Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafr El-Shaikh, 33516, Egypt
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28
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Luo Z, Luo Y, Liang X, Lyu Q, Meng F, Chen X, Wang Y, Fang W, Li A, Zhou D. Alantolactone-Loaded Pegylated Prodrug Nanocarriers for Synergistic Treatment of Cisplatin-Resistant Ovarian Cancer via Reactivating Mitochondrial Apoptotic Pathway. ACS Biomater Sci Eng 2022; 8:2526-2536. [PMID: 35612599 DOI: 10.1021/acsbiomaterials.2c00316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Ovarian cancer (OV) seriously damages women's health because of refractory OV and the development of platinum (Pt) resistance. New treatment strategies are urgently needed to deal with the treatment of cisplatin-resistant OV. Here, a reduction-sensitive pegylated Pt(IV) prodrug was synthesized by amidation of methoxy polyethylene glycol amine (PEG750-NH2) with monocarboxylic Pt(IV) prodrug (Pt(IV)-COOH). Then alantolactone (AL) loaded PEG-Pt(IV) nanocarriers (NP(Pt)@AL) were prepared. In the cisplatin-resistant model of OV, cancer cells actively ingest NP(Pt)@AL through endocytosis, and AL and Pt(II) were disintegrated and released under high intracellular reductant condition. The activity of thioredoxin reductase 1 (TrxR1) inhibited by AL and the adducts of Pt(II) with mitochondrial DNA (mDNA) can costimulate reactive oxygen species (ROS) and reactivate the mitochondrial pathway of apoptosis. Meanwhile, Pt(II) binds with nuclear DNA (nDNA) to jointly promote cell apoptosis. Both in vitro and in vivo results demonstrated that NP(Pt)@AL could effectively reverse the drug resistance and displayed excellent synergistic therapeutic efficacy on platinum-resistant OV with high safety. Therefore, reactivation of the mitochondrial pathway of apoptosis would be a potential strategy to improve the therapeutic effect of Pt-based chemotherapy and even reverse drug resistance.
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Affiliation(s)
- Zhijian Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, People's Republic of China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Yantao Luo
- Huidong County Maternal and Child Health Service Center, Huizhou 516300, People's Republic of China
| | - Xiaoling Liang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Qingyang Lyu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Fanliang Meng
- The Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Xuncai Chen
- School of Forensic Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Yupeng Wang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Weiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, People's Republic of China
| | - Aimin Li
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, People's Republic of China
| | - Dongfang Zhou
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, People's Republic of China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
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29
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Országhová Z, Kalavska K, Mego M, Chovanec M. Overcoming Chemotherapy Resistance in Germ Cell Tumors. Biomedicines 2022; 10:biomedicines10050972. [PMID: 35625709 PMCID: PMC9139090 DOI: 10.3390/biomedicines10050972] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 12/03/2022] Open
Abstract
Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance.
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Affiliation(s)
- Zuzana Országhová
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
| | - Katarina Kalavska
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia;
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy Sciences, 845 05 Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia;
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
- Correspondence:
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30
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Wang Y, Xie H, Wu Y, Xu S, Li Y, Li J, Xu X, Wang S, Li Y, Zhang Z. Bioinspired Lipoproteins of Furoxans-Oxaliplatin Remodel Physical Barriers in Tumor to Potentiate T-Cell Infiltration. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2110614. [PMID: 35092711 DOI: 10.1002/adma.202110614] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/21/2022] [Indexed: 05/21/2023]
Abstract
The infiltration of cytotoxic T lymphocytes (CTLs) in tumors is critically challenged by the intricate intratumor physical barriers, which is emerging as an important issue of anticancer immunotherapy. Herein, a reduction-sensitive nitric oxide donor conjugate of furoxans-oxaliplatin is synthesized and a stroma-cell-accessible bioinspired lipoprotein system (S-LFO) is designed, aiming to facilitate CTL infiltration in tumors for anticancer immunotherapy. S-LFO treatment significantly promotes tumor vessel normalization and eliminates multiple components of tumor stroma, ultimately producing a 2.96-fold, 5.02-fold, and 8.65-fold increase of CD3+ CD8+ T cells, their interferon-γ- and granzyme B-expressing subtypes when comparing to the negative control, and considerably facilitating their trafficking to the cancer cell regions in tumors. Moreover, the combination of S-LFO with an antiprogrammed death ligand-1 produces notable therapeutic benefits of retarded tumor growth and extends survivals in three murine tumor models. Therefore, this study provides an encouraging strategy of remodeling the intratumor physical barriers to potentiate CTL infiltration for anticancer immunotherapy.
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Affiliation(s)
- Yuqi Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China
| | - Honglei Xie
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, 264000, China
| | - Yao Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Shuzhou Xu
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, 264000, China
| | - Yongping Li
- Department of Breast Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Jie Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiaoxuan Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Siling Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China
| | - Yaping Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264005, China
| | - Zhiwen Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, 264000, China
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31
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Bisdemethoxycurcumin sensitizes the response of cisplatin resistant non-small cell lung carcinoma cell lines by activating apoptosis and autophagy. J Nutr Biochem 2022; 106:109003. [PMID: 35346827 DOI: 10.1016/j.jnutbio.2022.109003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/24/2021] [Accepted: 02/25/2022] [Indexed: 01/11/2023]
Abstract
Lung cancer belongs to the most frequent and deadliest cancer types worldwide, non-small cell lung carcinoma (NSCLC) being the most frequent type. Development of chemoresistance in NSCLC patients is common and responsible for bad outcome. Curcuminoids are naturally occurring substances with prominent cytotoxic effects in different cancer cells. Here we analyzed influence of bisdemethoxycurcumin (BDMC) on phenotype and molecular mechanisms in cisplatin-sensitive NSCLC cell lines (A549 and H460) and their cisplatin-resistant counterparts. NSCLC cell lines were exposed to BDMC and analyzed by cell viability, proliferation, and motility assays, as well as fluorescence-activated cell sorting. Immunoblotting was assessed to detect apoptosis and autophagy. Colony-formation assay and multicellular tumor spheroid model were used to investigate the effects of BDMC. Expression levels of different Hedgehog-pathway genes were determined by RT-qPCR analysis. We identified substantial cytotoxic effects of BDMC on NSCLC cells in general and on cisplatin-resistant NSCLC cells in special. BDMC markedly decreased the cell viability by inducing apoptosis and autophagy in a cell-type specific manner. BDMC emphasized cisplatin-induced cell death and inhibited cell cycle progression of cisplatin-resistant NSCLC cells. Scratch-closure, colony formation, and multicellular spheroid growth in cisplatin-resistant NSCLC cell lines were inhibited by BDMC. Expression profile analyses of different Hedgehog-pathway regulatory genes showed that Gli1, the mean transcriptional regulator of this pathway, was markedly decreased upon the BDMC treatment, this decrement being most prominent in cisplatin-resistant cells. Our data identified BDMC as a potent substance that may be suitable for combined cisplatin-based therapy in cisplatin-resistant subpopulation of NSCLC patients.
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Asadi MR, Moslehian MS, Sabaie H, Poornabi M, Ghasemi E, Hassani M, Hussen BM, Taheri M, Rezazadeh M. Stress Granules in the Anti-Cancer Medications Mechanism of Action: A Systematic Scoping Review. Front Oncol 2021; 11:797549. [PMID: 35004322 PMCID: PMC8739770 DOI: 10.3389/fonc.2021.797549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/08/2021] [Indexed: 12/16/2022] Open
Abstract
Stress granule (SG) formation is a well-known cellular mechanism for minimizing stress-related damage and increasing cell survival. In addition to playing a critical role in the stress response, SGs have emerged as critical mediators in human health. It seems logical that SGs play a key role in cancer cell formation, development, and metastasis. Recent studies have shown that many SG components contribute to the anti-cancer medications' responses through tumor-associated signaling pathways and other mechanisms. SG proteins are known for their involvement in the translation process, control of mRNA stability, and capacity to function in both the cytoplasm and nucleus. The current systematic review aimed to include all research on the impact of SGs on the mechanism of action of anti-cancer medications and was conducted using a six-stage methodological framework and the PRISMA guideline. Prior to October 2021, a systematic search of seven databases for eligible articles was performed. Following the review of the publications, the collected data were subjected to quantitative and qualitative analysis. Notably, Bortezomib, Sorafenib, Oxaliplatin, 5-fluorouracil, Cisplatin, and Doxorubicin accounted for the majority of the medications examined in the studies. Overall, this systematic scoping review attempts to demonstrate and give a complete overview of the function of SGs in the mechanism of action of anti-cancer medications by evaluating all research.
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Affiliation(s)
- Mohammad Reza Asadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hani Sabaie
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziye Poornabi
- Student Research Committee, School of Medicine, Shahroud University of Medical Science, Shahroud, Iran
| | - Elham Ghasemi
- Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mehdi Hassani
- Student Research Committee, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Maryam Rezazadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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Wu G, Peng H, Tang M, Yang M, Wang J, Hu Y, Li Z, Li J, Li Z, Song L. ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine 2021; 71:103558. [PMID: 34521054 PMCID: PMC8441092 DOI: 10.1016/j.ebiom.2021.103558] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 01/07/2023] Open
Abstract
Background Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. Methods ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. Findings ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. Interpretation These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. Funding This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.
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Affiliation(s)
- Geyan Wu
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hu Peng
- Department of Gynecological Oncology, Hubei Cancer Hospital, Wuhan 430071, China
| | - Miaoling Tang
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Meisongzhu Yang
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jun Wang
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming 650118, China
| | - Yameng Hu
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ziwen Li
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jun Li
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zheng Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming 650118, China.
| | - Libing Song
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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Xian C, Chen H, Xiong F, Fang Y, Huang H, Wu J. Platinum-based chemotherapy via nanocarriers and co-delivery of multiple drugs. Biomater Sci 2021; 9:6023-6036. [PMID: 34323260 DOI: 10.1039/d1bm00879j] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Platinum-based anticancer drugs can inhibit the growth of cancer cells by disrupting DNA replication, which makes them widely applicable in clinics for treating tumors and cancers. However, owing to the intrinsic or acquired drug resistance and severe side effects caused in the treatment, their successful clinical applications have been limited. Various strategies have been used to address these challenges. Nanocarriers have been used for platinum drug delivery because they can be effectively deposited in tumor tissues to reduce the damage to normal organs for an enhanced permeability and retention (EPR) effect. Furthermore, for synergizing the function of platinum-based drugs with different mechanisms to decrease the toxicities, multicomponent chemotherapy has become an imperative strategy in clinical cancer treatments. This review aims to introduce the mechanisms of action and limitations of platinum-based drugs in clinics, followed by providing the current advancement of nanocarriers including lipids, polymers, dendrimers, micelles and albumin for platinum drug delivery in cancer treatments. In addition, multicomponent chemotherapy based on platinum drugs is introduced in detail. Finally, the prospects of multicomponent chemotherapy for cancer treatment are discussed as well.
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Affiliation(s)
- Caihong Xian
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518057, China
| | - Haolin Chen
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518057, China
| | - Fei Xiong
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518057, China
| | - Yifen Fang
- The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou 510180, China
| | - Hai Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jun Wu
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518057, China
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Chen Y, Li ZH, Pan P, Zeng RY, Zhang XZ. Tumor-Specific ONOO - Nanogenerator for Improved Drug Delivery and Enhanced Chemotherapy of Tumor. ACS NANO 2021; 15:11514-11525. [PMID: 34275285 DOI: 10.1021/acsnano.1c01312] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Multiple biological barriers in solid tumors severely restrict the penetration of nanomedicines, which is a main cause for therapeutic failure in traditional tumor treatment. Here, a tumor-specific nanogenerator of peroxynitrite (ONOO-), prepared by loading cisplatin and sodium nitroprusside into poly(d,l-lactide-co-glycolide) polymersomes, was designed to improve drug delivery and enhance tumor chemotherapy. After a cascade of nicotinamide adenine dinucleotide phosphate oxidases catalysis and glutathione reduction, the nanogenerator, namely, PMCS, could selectively induce the generation of ONOO- in tumor. The generated ONOO- could not only strengthen vascular permeability significantly but also improve the accumulation and penetration of PMCS in tumor by activating matrix metalloproteinases-mediated degradation of extracellular matrix. Along with endocytosis, PMCS released cisplatin to induce tumor cell apoptosis. Moreover, free cisplatin liberated from dead cells infected neighboring tumor cells quickly via ONOO--mediated up-regulated copper transporter 1, further amplifying chemotherapeutic efficacy. This study advances ONOO- as a potent modality to address the main issues of therapeutic delivery, including but not limited to chemotherapy.
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Affiliation(s)
- Ying Chen
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Zi-Hao Li
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Pei Pan
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Run-Yao Zeng
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
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Kuang X, Hu Y, Chi D, Zhang H, He Z, Jiang Y, Wang Y. Self-stabilized Pt(IV) amphiphiles by precise regulation of branch length for enhanced chemotherapy. Int J Pharm 2021; 606:120923. [PMID: 34303822 DOI: 10.1016/j.ijpharm.2021.120923] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/04/2021] [Accepted: 07/20/2021] [Indexed: 11/29/2022]
Abstract
A surge of platinum(IV) compounds are utilized or investigated in cancer treatment but their therapeutic outcomes have been greatly compromised by remaining adverse effects and limited antitumor performance, attributable to nonspecific distribution and insufficient activation in tumor site. Herein, we designed a series of disulfide bond introduced Pt(IV)-lipid prodrugs with different branch length, all of which are able to self-stabilize into nanomedicine and be activated by high intracellular glutathione (GSH) level. The impact of precise modification of these prodrugs on their assembly stability, pharmacokinetics and cytotoxicity was probed to establish a connection between chemical structure and antiproliferation efficiency. With optimal assembly manner and delivery efficacy, the longest axial branched Pt(IV) prodrug CSS18 exhibited the most impressive therapeutic outcome, providing a potential path to more efficient nanocarriers for chemotherapeutic agents by chemical modulation and, giving insights into the rational design of reduction responsive platinum delivery system.
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Affiliation(s)
- Xiao Kuang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yuting Hu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dongxu Chi
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Haolin Zhang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhonggui He
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yiguo Jiang
- Department of Pharmacy, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China.
| | - Yongjun Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
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Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity. Int J Mol Sci 2021; 22:ijms22147568. [PMID: 34299199 PMCID: PMC8306828 DOI: 10.3390/ijms22147568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 11/17/2022] Open
Abstract
Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.
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Abstract
Metal complexes have been widely used for applications in the chemical and physical sciences due to their unique electronic and stereochemical properties. For decades the use of metal complexes for medicinal applications has been postulated and demonstrated. The distinct characteristics of metal complexes, including their molecular geometries (that are not readily accessed by organic molecules), as well as their ligand exchange, redox, catalytic, and photophysical reactions, give these compounds the potential to interact and react with biomolecules in unique ways and by distinct mechanisms of action. Herein, the potential of metal complexes to act as components bioactive therapeutic compounds is discussed.
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Affiliation(s)
| | | | - Seth M. Cohen
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
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Marzo T, La Mendola D. The Effects on Angiogenesis of Relevant Inorganic Chemotherapeutics. Curr Top Med Chem 2021; 21:73-86. [PMID: 33243124 DOI: 10.2174/1568026620666201126163436] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022]
Abstract
Angiogenesis is a key process allowing the formation of blood vessels. It is crucial for all the tissues and organs, ensuring their function and growth. Angiogenesis is finely controlled by several mechanisms involving complex interactions between pro- or antiangiogenic factors, and an imbalance in this control chain may result in pathological conditions. Metals as copper, zinc and iron cover an essential role in regulating angiogenesis, thus therapies having physiological metals as target have been proposed. In addition, some complexes of heavier metal ions (e.g., Pt, Au, Ru) are currently used as established or experimental anticancer agents targeting genomic or non-genomic targets. These molecules may affect the angiogenic mechanisms determining different effects that have been only poorly and non-systematically investigated so far. Accordingly, in this review article, we aim to recapitulate the impact on the angiogenic process of some reference anticancer drugs, and how it is connected to the overall pharmacological effects. In addition, we highlight how the activity of these drugs can be related to the role of biological essential metal ions. Overall, this may allow a deeper description and understanding of the antineoplastic activity of both approved or experimental metal complexes, providing important insights for the synthesis of new inorganic drugs able to overcome resistance and recurrence phenomena.
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Affiliation(s)
- Tiziano Marzo
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126, Pisa, Italy
| | - Diego La Mendola
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126, Pisa, Italy
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40
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Wang L, Zhao X, Fu J, Xu W, Yuan J. The Role of Tumour Metabolism in Cisplatin Resistance. Front Mol Biosci 2021; 8:691795. [PMID: 34250022 PMCID: PMC8261055 DOI: 10.3389/fmolb.2021.691795] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022] Open
Abstract
Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.
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Affiliation(s)
- Lude Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xiaoya Zhao
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jianlie Yuan
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Eckert MA, Orozco C, Xiao J, Javellana M, Lengyel E. The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment. Cancers (Basel) 2021; 13:3136. [PMID: 34201616 PMCID: PMC8268261 DOI: 10.3390/cancers13133136] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022] Open
Abstract
High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.
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Affiliation(s)
| | | | | | | | - Ernst Lengyel
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA; (M.A.E.); (C.O.); (J.X.); (M.J.)
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Boztepe T, Castro GR, León IE. Lipid, polymeric, inorganic-based drug delivery applications for platinum-based anticancer drugs. Int J Pharm 2021; 605:120788. [PMID: 34116182 DOI: 10.1016/j.ijpharm.2021.120788] [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: 12/15/2020] [Revised: 06/02/2021] [Accepted: 06/05/2021] [Indexed: 12/13/2022]
Abstract
The three main FDA-approved platinum drugs in chemotherapy such as carboplatin, cisplatin, and oxaliplatin are extensively applied in cancer treatments. Although the clinical applications of platinum-based drugs are extremely effective, their toxicity profile restricts their extensive application. Therefore, recent studies focus on developing new platinum drug formulations, expanding the therapeutic aspect. In this sense, recent advances in the development of novel drug delivery carriers will help with the increase of drug stability and biodisponibility, concomitantly with the reduction of drug efflux and undesirable secondary toxic effects of platinum compounds. The present review describes the state of the art of platinum drugs with their biological effects, pre- and clinical studies, and novel drug delivery nanodevices based on lipids, polymers, and inorganic.
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Affiliation(s)
- Tugce Boztepe
- Laboratorio de Nanobiomateriales, CINDEFI - Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata-CONICET (CCT La Plata), Calle 47 y 115, B1900AJL La Plata, Argentina
| | - Guillermo R Castro
- Laboratorio de Nanobiomateriales, CINDEFI - Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata-CONICET (CCT La Plata), Calle 47 y 115, B1900AJL La Plata, Argentina; Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC), Partner Laboratory of the Max Planck Institute for Biophysical Chemistry (MPIbpC, MPG), Centro de Estudios Interdisciplinarios (CEI), Universidad Nacional de Rosario, Maipú 1065, S2000 Rosario, Santa Fe, Argentina.
| | - Ignacio E León
- Centro de Química Inorgánica, CEQUINOR (CONICET-UNLP), Bv. 120 1465, La Plata, Argentina.
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Interference between copper transport systems and platinum drugs. Semin Cancer Biol 2021; 76:173-188. [PMID: 34058339 DOI: 10.1016/j.semcancer.2021.05.023] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/17/2021] [Indexed: 01/06/2023]
Abstract
Cisplatin, or cis-diamminedichloridoplatinum(II) cis-[PtCl2(NH3)2], is a platinum-based anticancer drug largely used for the treatment of various types of cancers, including testicular, ovarian and colorectal carcinomas, sarcomas, and lymphomas. Together with other platinum-based drugs, cisplatin triggers malignant cell death by binding to nuclear DNA, which appears to be the ultimate target. In addition to passive diffusion across the cell membrane, other transport systems, including endocytosis and some active or facilitated transport mechanisms, are currently proposed to play a pivotal role in the uptake of platinum-based drugs. In this review, an updated view of the current literature regarding the intracellular transport and processing of cisplatin will be presented, with special emphasis on the plasma membrane copper permease CTR1, the Cu-transporting ATPases, ATP7A and ATP7B, located in the trans-Golgi network, and the soluble copper chaperone ATOX1. Their role in eliciting cisplatin efficacy and their exploitation as pharmacological targets will be addressed.
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Mollaei M, Hassan ZM, Khorshidi F, Langroudi L. Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells? Transl Oncol 2021; 14:101056. [PMID: 33684837 PMCID: PMC7938256 DOI: 10.1016/j.tranon.2021.101056] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
Chemotherapeutic drugs kill cancer cells or control their progression all over the patient's body, while radiation- and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresistance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conventional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.
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Affiliation(s)
- Mojtaba Mollaei
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran.
| | | | - Fatemeh Khorshidi
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran; Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Langroudi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Kuang X, Chi D, Li J, Guo C, Yang Y, Zhou S, Luo C, Liu H, He Z, Wang Y. Disulfide bond based cascade reduction-responsive Pt(IV) nanoassemblies for improved anti-tumor efficiency and biosafety. Colloids Surf B Biointerfaces 2021; 203:111766. [PMID: 33866279 DOI: 10.1016/j.colsurfb.2021.111766] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/18/2021] [Accepted: 04/10/2021] [Indexed: 12/11/2022]
Abstract
The platinum-based drugs prevail in the therapy of malignant tumors treatment. However, their clinical outcomes have been heavily restricted by severe systemic toxicities. To ensure biosafety and efficiency, herein, we constructed a disulfide bond inserted Pt(IV) self-assembled nanoplatform that is selectively activated by rich glutathione (GSH) in tumor site. Disulfide bond was introduced into the conjugates of oxaliplatin (IV) and oleic acid (OA) which conferred cascade reduction-responsiveness to nanoassemblies. Disulfide bond cleavage and reduction of Pt(IV) center occur sequentially as a cascade process. In comparison to oxaliplatin solution, Pt(IV) nanoparticles (NPs) achieved prolonged blood circulation and higher maximum tolerated doses. Furthermore, Oxa(IV)-SS-OA prodrug NPs exhibited potent anti-tumor efficiency against 4T1 cells and low toxicities in other normal tissues, which offers a promising nano-platform for potential clinical application.
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Affiliation(s)
- Xiao Kuang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dongxu Chi
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jinbo Li
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Chunlin Guo
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yinxian Yang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Shuang Zhou
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Cong Luo
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Hongzhuo Liu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhonggui He
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yongjun Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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MacDonagh L, Santiago RM, Gray SG, Breen E, Cuffe S, Finn SP, O'Byrne KJ, Barr MP. Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin. Transl Oncol 2021; 14:101025. [PMID: 33550205 PMCID: PMC7868629 DOI: 10.1016/j.tranon.2021.101025] [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: 07/22/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/23/2022] Open
Abstract
Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours.
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Affiliation(s)
- Lauren MacDonagh
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland.
| | - Rhyla Mae Santiago
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland.
| | - Steven G Gray
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland.
| | - Eamon Breen
- Flow Cytometry Facility, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, Ireland.
| | - Sinead Cuffe
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland; Medical Oncology Department, St James's Hospital, Dublin, Ireland.
| | - Stephen P Finn
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland; Histopathology Department, St James's Hospital & Trinity College Dublin, Ireland.
| | - Kenneth J O'Byrne
- Cancer & Ageing Research Program, Queensland University of Technology, Brisbane, Australia.
| | - Martin P Barr
- Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland.
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The Affinity of Carboplatin to B-Vitamins and Nucleobases. Int J Mol Sci 2021; 22:ijms22073634. [PMID: 33807309 PMCID: PMC8037198 DOI: 10.3390/ijms22073634] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 03/26/2021] [Accepted: 03/28/2021] [Indexed: 11/17/2022] Open
Abstract
Platinum compounds have found wide application in the treatment of various types of cancer and carboplatin is one of the main platinum-based drugs used as antitumor agents. The anticancer activity of carboplatin arises from interacting with DNA and inducing programmed cell death. However, such interactions may occur with other chemical compounds, such as vitamins containing aromatic rings with lone-pair orbitals, which reduces the anti-cancer effect of carboplatin. The most important aspect of the conducted research was related to the evaluation of carboplatin affinity to vitamins from the B group and the potential impact of such interactions on the reduction of therapeutic capabilities of carboplatin in anticancer therapy. Realized computations, including estimation of Gibbs Free Energies, allowed for the identification of the most reactive molecule, namely vitamin B6 (pyridoxal phosphate). In this case, the computational estimations indicating carboplatin reactivity were confirmed by spectrophotometric measurements.
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48
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Hassanen EI, Korany RMS, Bakeer AM. Cisplatin-conjugated gold nanoparticles-based drug delivery system for targeting hepatic tumors. J Biochem Mol Toxicol 2021; 35:e22722. [PMID: 33484050 DOI: 10.1002/jbt.22722] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 12/01/2020] [Accepted: 01/09/2021] [Indexed: 01/19/2023]
Abstract
Cisplatin is a highly cytotoxic anticarcinogenic drug used to treat several kinds of solid tumors such as liver tumors. With the increase in the incidences associated with hepatic tumors and a lack of selectivity of cisplatin to cancer cells, it is important to explore new therapeutic strategies against them. The present study was designed to verify the ability of gold nanoparticles (GNPs) to improve the hepatotherapeutic effect of cisplatin against DENA-induced hepatic tumors and to declare its ability to reduce the renal toxicity induced by cisplatin. Forty male Wistar rats were divided into two groups (n = 20): Group (A)-negative control and group (B)-model of hepatocellular tumor induction. After 4 months, each group was subdivided into four subgroups as the following: Group (1) received normal saline, Group (2) was treated by cisplatin, Group (3) was treated by GNPs, Group (4) was treated by GNPs-cisplatin conjugates. Our results revealed a marked elevation in liver and kidney function tests and oxidant levels with a reduction in antioxidant levels in the DENA-administrated group. Remarkable histopathological alterations in the liver and kidney tissue sections were observed and confirmed by the overexpression of the immunohistochemical staining of placental glutathione S-transferase, Hep Par 1, and proliferating cell nuclear antigen. Noticeable improvements in all the measurable toxicological parameters were recorded in the group treated with either GNPs or GNPs-cisplatin conjugate not observed in the group treated with cisplatin. We can conclude that GNPs not only improve the distribution of cisplatin, targeting it to the site of tumors, but it also reduces the renal toxicity induced by cisplatin, which are the primary concerns in cancer therapy.
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Affiliation(s)
| | | | - Adel M Bakeer
- Department of Pathology, Cairo University, Giza, Egypt
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Taheri M, Shoorei H, Tondro Anamag F, Ghafouri-Fard S, Dinger ME. LncRNAs and miRNAs participate in determination of sensitivity of cancer cells to cisplatin. Exp Mol Pathol 2021; 123:104602. [PMID: 33422487 DOI: 10.1016/j.yexmp.2021.104602] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023]
Abstract
Cisplatin is an extensively used chemotherapeutic substance for various types of human malignancies including sarcomas, carcinomas and lymphomas. Yet, the vast application of this drug is hampered by the emergence of chemoresistance in some treated patients. Several mechanisms such as degradation of the membrane transporters by cisplatin have been implicated in the pathogenesis of this event. Recent researches have also indicated the role of long non-coding RNAs (lncRNAs) as well as micoRNAs (miRNAs) in the emergence of resistance to cisplatin in several cancer types. For instance, up-regulation of miR-21 has been associated with resistance to this agent in ovarian cancer, oral squamous cell cancer, gastric malignancy and non-small cell lung cancer (NSCLC). On the other hand, down-regulation of miR-218 has been implicated in emergence of chemoresistance in breast cancer and esophageal squamous cell carcinoma. MALAT1 is implicated in the chemoresistance of bladder cancer cells, NSCLC, gastric cancer and cervical cancer. Most notably, the expression profile of resistance-associated miRNAs and lncRNAs can predict overall survival of cancer patients. Mechanistic assays have revealed that interference with expression of some miRNAs and lncRNAs can reverse the resistance phenotype in cancer cells. In this paper, we review the scientific writings on the role of lncRNAs and miRNAs in the evolution of chemoresistance to cisplatin in cancer cells.
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Affiliation(s)
- Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
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50
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Xie P, Wang Y, Wei D, Zhang L, Zhang B, Xiao H, Song H, Mao X. Nanoparticle-based drug delivery systems with platinum drugs for overcoming cancer drug resistance. J Mater Chem B 2021; 9:5173-5194. [PMID: 34116565 DOI: 10.1039/d1tb00753j] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Platinum drugs are commonly used in cancer therapy, but their therapeutic outcomes have been significantly compromised by the drug resistance of cancer cells. To this end, intensive efforts have been made to develop nanoparticle-based drug delivery systems for platinum drugs, due to their multifunctionality in delivering drugs, in modulating the tumor microenvironment, and in integrating additional genes, proteins, and small molecules to overcome chemoresistance in cancers. To facilitate the clinical application of these promising nanoparticle-based platinum drug delivery systems, this paper summarizes the common mechanisms for chemoresistance towards platinum drugs, the advantages of nanoparticles in drug delivery, and recent strategies of nanoparticle-based platinum drug delivery. Furthermore, we discuss how to design delivery platforms more effectively to overcome chemoresistance in cancers, thereby improving the efficacy of platinum-based chemotherapy.
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Affiliation(s)
- Peng Xie
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. and Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
| | - Yushu Wang
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Dengshuai Wei
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
| | - Lingpu Zhang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
| | - Bin Zhang
- XJTU-Oxford International Joint Laboratory for Catalysis, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
| | - Haiqin Song
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
| | - Xinzhan Mao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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