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Beretta GL, Cassinelli G, Rossi G, Azzariti A, Corbeau I, Tosi D, Perego P. Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies. Drug Resist Updat 2025; 81:101223. [PMID: 40086175 DOI: 10.1016/j.drup.2025.101223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/16/2025]
Abstract
Taxanes are effective in several solid tumors. Paclitaxel, the main clinically available taxane, was approved in the early nineties, for the treatment of ovarian cancer and later on, together with the analogs docetaxel and cabazitaxel, for other malignancies. By interfering with microtubule function and impairing the separation of sister cells at mitosis, taxanes act as antimitotic agents, thereby counteracting the high proliferation rate of cancer cells. The action of taxanes goes beyond their antimitotic function because their main cellular targets, the microtubules, participate in multiple processes such as intracellular transport and cell shape maintenance. The clinical efficacy of taxanes is limited by the development of multiple resistance mechanisms. Among these, extracellular vesicles have emerged as new players. In addition, taxane metronomic schedules shows an impact on the tumor microenvironment reflected by antiangiogenic and immunomodulatory effects, an aspect of growing interest considering their inclusion in treatment regimens with immunotherapeutics. Preclinical studies have paved the bases for synergistic combinations of taxanes both with conventional and targeted agents. A variety of drug delivery strategies have provided novel opportunities to increase the drug activity. The ability of taxanes to orchestrate different cellular effects amenable to modulation suggests novel options to improve cures in lethal malignancies.
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Affiliation(s)
- Giovanni Luca Beretta
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy.
| | - Giuliana Cassinelli
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy.
| | - Giacomina Rossi
- Unit of Neurology 8, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
| | - Amalia Azzariti
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, V.le O. Flacco, 65, Bari 70124, Italy.
| | - Iléana Corbeau
- Early Clinical Trial Unit, Medical Oncology Department, Institut régional du Cancer de Montpellier, Inserm U1194, Montpellier University, 208, rue de Apothicaires, 34298 Montpellier, France; Fondazione Gianni Bonadonna, via Bertani, 14, Milan 20154, Italy.
| | - Diego Tosi
- Early Clinical Trial Unit, Medical Oncology Department, Institut régional du Cancer de Montpellier, Inserm U1194, Montpellier University, 208, rue de Apothicaires, 34298 Montpellier, France; Fondazione Gianni Bonadonna, via Bertani, 14, Milan 20154, Italy.
| | - Paola Perego
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy.
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Aydin H, Ozcelikkale A, Acar A. Exploiting Matrix Stiffness to Overcome Drug Resistance. ACS Biomater Sci Eng 2024; 10:4682-4700. [PMID: 38967485 PMCID: PMC11322920 DOI: 10.1021/acsbiomaterials.4c00445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 07/06/2024]
Abstract
Drug resistance is arguably one of the biggest challenges facing cancer research today. Understanding the underlying mechanisms of drug resistance in tumor progression and metastasis are essential in developing better treatment modalities. Given the matrix stiffness affecting the mechanotransduction capabilities of cancer cells, characterization of the related signal transduction pathways can provide a better understanding for developing novel therapeutic strategies. In this review, we aimed to summarize the recent advancements in tumor matrix biology in parallel to therapeutic approaches targeting matrix stiffness and its consequences in cellular processes in tumor progression and metastasis. The cellular processes governed by signal transduction pathways and their aberrant activation may result in activating the epithelial-to-mesenchymal transition, cancer stemness, and autophagy, which can be attributed to drug resistance. Developing therapeutic strategies to target these cellular processes in cancer biology will offer novel therapeutic approaches to tailor better personalized treatment modalities for clinical studies.
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Affiliation(s)
- Hakan
Berk Aydin
- Department
of Biological Sciences, Middle East Technical
University, 06800, Ankara, Turkey
| | - Altug Ozcelikkale
- Department
of Mechanical Engineering, Middle East Technical
University, 06800, Ankara, Turkey
- Graduate
Program of Biomedical Engineering, Middle
East Technical University, 06800, Ankara, Turkey
| | - Ahmet Acar
- Department
of Biological Sciences, Middle East Technical
University, 06800, Ankara, Turkey
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Daniel P, Balušíková K, Truksa J, Černý J, Jaček M, Jelínek M, Mulenga MJV, Voráčová K, Chen L, Wei L, Sun Y, Ojima I, Kovář J. Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells. Toxicol Appl Pharmacol 2024; 489:116993. [PMID: 38870637 PMCID: PMC11257372 DOI: 10.1016/j.taap.2024.116993] [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: 01/24/2024] [Revised: 04/25/2024] [Accepted: 06/05/2024] [Indexed: 06/15/2024]
Abstract
We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.
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Affiliation(s)
- Petr Daniel
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Kamila Balušíková
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jaroslav Truksa
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic; Laboratory of Tumor Resistance, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Centre, Vestec, Czech Republic
| | - Jiří Černý
- Laboratory of Structural Bioinformatics of Proteins, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Centre, Vestec, Czech Republic
| | - Martin Jaček
- Department of Hygiene, Epidemiology and Preventive Medicine, Third Faculty of Medicine, Charles Univesity, Prague, Czech Republic
| | - Michael Jelínek
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Mutale Jane Vobruba Mulenga
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kateřina Voráčová
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Lei Chen
- Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Longfei Wei
- Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Yi Sun
- Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Iwao Ojima
- Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Jan Kovář
- Division of Cell and Molecular Biology, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
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Cai W, Rong D, Ding J, Zhang X, Wang Y, Fang Y, Xiao J, Yang S, Wang H. Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells. Cancer Cell Int 2024; 24:249. [PMID: 39020371 PMCID: PMC11256575 DOI: 10.1186/s12935-024-03443-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.
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Affiliation(s)
- Wanhua Cai
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Dade Rong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
- Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Jiayu Ding
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Xiaomei Zhang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
| | - Yuwei Wang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
- School of Medicine, Xizang Minzu University, No.6 Wenhui Donglu, Xianyang, 712082, China
| | - Ying Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Jing Xiao
- Department of Clinical Laboratory, Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, China.
| | - Shulan Yang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China.
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China.
- School of Medicine, Xizang Minzu University, No.6 Wenhui Donglu, Xianyang, 712082, China.
- Clinical Medical Research Centre for Plateau Gastroenterological Disease of Xizang Autonomous Region, Xizang Minzu University, Xianyang 712082, China.
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Długosz-Pokorska A, Janecki T, Janecka A, Gach-Janczak K. New uracil analog as inhibitor/modulator of ABC transporters or/and NF-κB in taxol-resistant MCF-7/Tx cell line. J Cancer Res Clin Oncol 2024; 150:328. [PMID: 38914845 PMCID: PMC11196363 DOI: 10.1007/s00432-024-05833-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/03/2024] [Indexed: 06/26/2024]
Abstract
PURPOSE The global increase in breast cancer cases necessitates ongoing exploration of advanced therapies. Taxol (Tx), an initial breast cancer treatment, induces mitotic arrest but faces limitations due to side effects and the development of resistance. Addressing Tx resistance involves understanding the complex molecular mechanisms, including alterations in tubulin dynamics, NF-κB signaling, and overexpression of ABC transporters (ABCB1 and ABCG2), leading to multidrug resistance (MDR). METHODS Real-time PCR and ELISA kits were used to analyze ABCB1, ABCG2 and NF-κB gene and protein expression levels, respectively. An MDR test assessed the resistance cell phenotype. RESULTS MCF-7/Tx cells exhibited a 24-fold higher resistance to Tx. Real-time PCR and ELISA analysis revealed the upregulation of ABCB1, ABCG2, and NF-κB. U-359 significantly downregulated both ABCB1 and ABCG2 gene and protein levels. Co-incubation with Tx and U-359 further decreased the mRNA and protein expression of these transporters. The MDR test indicated that U-359 increased MDR dye retention, suggesting its potential as an MDR inhibitor. U-359 and Tx, either individually or combined, modulated NF-κBp65 protein levels. CONCLUSION The development of a Taxol-resistant MCF-7 cell line provided valuable insights. U-359 demonstrated effectiveness in reducing the expression of ABC transporters and NF-κB, suggesting a potential solution for overcoming multidrug resistance in breast cancer cells. The study recommends a strategy to enhance the sensitivity of cancer cells to chemotherapy by integrating U-359 with traditional drugs.
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MESH Headings
- Humans
- Paclitaxel/pharmacology
- Drug Resistance, Neoplasm/drug effects
- NF-kappa B/metabolism
- MCF-7 Cells
- Female
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Antineoplastic Agents, Phytogenic/pharmacology
- Drug Resistance, Multiple/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
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Affiliation(s)
- Angelika Długosz-Pokorska
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
| | - Tomasz Janecki
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Lodz, Poland
| | - Anna Janecka
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Katarzyna Gach-Janczak
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
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Mahgoub TM, Jordan EJ, Mahdi AF, Oettl V, Huefner S, O'Donovan N, Crown J, Collins DM. Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells. Cancer Chemother Pharmacol 2024; 93:427-437. [PMID: 38226983 PMCID: PMC11043045 DOI: 10.1007/s00280-023-04624-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/20/2023] [Indexed: 01/17/2024]
Abstract
PURPOSE Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies. METHODS This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays. RESULTS Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC50 profile of ABT-751 was higher than the taxanes docetaxel and paclitaxel in the melanoma cell line panel, but fell within clinically achievable parameters. ABT-751 IC50 was not impacted by P-gp-overexpression in DKLP-A cells, which display strong resistance to the P-gp substrate taxanes compared to DLKP parental controls. The addition of ABT-751 to paclitaxel treatment significantly decreased cell proliferation, suggesting some reversal of MDR. ATPase activity assays suggest that ABT-751 is a potential BCRP substrate, with the ability to inhibit P-gp ATPase activity. CONCLUSION Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma.
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Affiliation(s)
- Thamir M Mahgoub
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Emmet J Jordan
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Amira F Mahdi
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
- School of Medicine, University of Limerick, Limerick, Ireland
| | - Veronika Oettl
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Stefanie Huefner
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Norma O'Donovan
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - John Crown
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
- Department of Medical Oncology, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Denis M Collins
- Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
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Sanchez Y, Vasquez Callejas MA, Miret NV, Rolandelli G, Costas C, Randi AS, Español A. Hexachlorobenzene as a differential modulator of the conventional and metronomic chemotherapy response in triple negative breast cancer cells. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:278-295. [PMID: 38745771 PMCID: PMC11090688 DOI: 10.37349/etat.2024.00218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 11/27/2023] [Indexed: 05/16/2024] Open
Abstract
Aim Triple negative breast cancer (TNBC) is usually treated with high doses of paclitaxel, whose effectiveness may be modulated by the action of environmental contaminants such as hexachlorobenzene. High doses of paclitaxel cause adverse effects such as low cellular selectivity and the generation of resistance to treatment due to an increase in the expression of multidrug resistance proteins (MRPs). These effects can be reduced using a metronomic administration scheme with low doses. This study aimed to investigate whether hexachlorobenzene modulates the response of cells to conventional chemotherapy with paclitaxel or metronomic chemotherapy with paclitaxel plus carbachol, as well as to study the participation of the MRP ATP-binding cassette transporter G2 (ABCG2) in human TNBC MDA-MB231 cells. Methods Cells were treated with hexachlorobenzene alone or in combination with conventional or metronomic chemotherapies. The effects of treatments on cell viability were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the nuclear factor kappa B pathway participation was evaluated using a selective inhibitor. ABCG2 expression and its modulation were determined by western blot. Results Results confirmed that paclitaxel reduces MDA-MB231 cell viability in a concentration-dependent manner. Results also showed that both conventional and metronomic chemotherapies reduced cell viability with similar efficacy. Although hexachlorobenzene did not modify cell viability per se, it did reverse the effect induced by the conventional chemotherapy, without affecting the efficacy of the metronomic chemotherapy. Additionally, a differential modulation of ABCG2 expression was determined, mediated by the nuclear factor kappa B pathway, which was directly related to the modulation of cell sensitivity to another cycle of paclitaxel treatment. Conclusions The findings indicate that, in human TNBC MDA-MB231 cells, in the presence of hexachlorobenzene, the metronomic combination of paclitaxel plus carbachol is more effective in affecting the tumor biology than the conventional therapeutic administration scheme of paclitaxel.
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Affiliation(s)
- Yamila Sanchez
- Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Mariana Abigail Vasquez Callejas
- Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Noelia Victoria Miret
- Laboratory of Biological Effects of Environmental Pollutants, Department of Human Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Gabino Rolandelli
- Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Catalina Costas
- Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Andrea Silvana Randi
- Laboratory of Biological Effects of Environmental Pollutants, Department of Human Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Alejandro Español
- Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina
- Department of Pharmacology, School of Medicine, University of Buenos Aires, Buenos Aires C1121ABG, Argentina
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8
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Giulietti M, Piva F, Cecati M, Maggio S, Guescini M, Saladino T, Scortichini L, Crocetti S, Caramanti M, Battelli N, Romagnoli E. Effects of Eribulin on the RNA Content of Extracellular Vesicles Released by Metastatic Breast Cancer Cells. Cells 2024; 13:479. [PMID: 38534323 PMCID: PMC10969587 DOI: 10.3390/cells13060479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 02/23/2024] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
Extracellular vesicles (EVs) are small lipid particles secreted by almost all human cells into the extracellular space. They perform the essential function of cell-to-cell communication, and their role in promoting breast cancer progression has been well demonstrated. It is known that EVs released by triple-negative and highly aggressive MDA-MB-231 breast cancer cells treated with paclitaxel, a microtubule-targeting agent (MTA), promoted chemoresistance in EV-recipient cells. Here, we studied the RNA content of EVs produced by the same MDA-MB-231 breast cancer cells treated with another MTA, eribulin mesylate. In particular, we analyzed the expression of different RNA species, including mRNAs, lncRNAs, miRNAs, snoRNAs, piRNAs and tRNA fragments by RNA-seq. Then, we performed differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and miRNA-target identification. Our findings demonstrate the possible involvement of EVs from eribulin-treated cells in the spread of chemoresistance, prompting the design of strategies that selectively target tumor EVs.
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Affiliation(s)
- Matteo Giulietti
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Francesco Piva
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Monia Cecati
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Serena Maggio
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Michele Guescini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Tiziana Saladino
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Laura Scortichini
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Sonia Crocetti
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Miriam Caramanti
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Nicola Battelli
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Emanuela Romagnoli
- Oncology Unit AST3, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
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9
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Miller JS, Bennett NE, Rhoades JA. Targeting hedgehog-driven mechanisms of drug-resistant cancers. Front Mol Biosci 2023; 10:1286090. [PMID: 37954979 PMCID: PMC10634604 DOI: 10.3389/fmolb.2023.1286090] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/09/2023] [Indexed: 11/14/2023] Open
Abstract
Due to the cellular plasticity that is inherent to cancer, the acquisition of resistance to therapy remains one of the biggest obstacles to patient care. In many patients, the surviving cancer cell subpopulation goes on to proliferate or metastasize, often as the result of dramatically altered cell signaling and transcriptional pathways. A notable example is the Hedgehog (Hh) signaling pathway, which is a driver of several cancer subtypes and aberrantly activated in a wide range of malignancies in response to therapy. This review will summarize the field's current understanding of the many roles played by Hh signaling in drug resistance and will include topics such as non-canonical activation of Gli proteins, amplification of genes which promote tolerance to chemotherapy, the use of hedgehog-targeted drugs and tool compounds, and remaining gaps in our knowledge of the transcriptional mechanisms at play.
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Affiliation(s)
- Jade S. Miller
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Pharmacology Training Program, Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Veterans Affairs, Nashville VA Medical Center, Tennessee Valley Healthcare System, Nashville, TN, United States
| | - Natalie E. Bennett
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Veterans Affairs, Nashville VA Medical Center, Tennessee Valley Healthcare System, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Julie A. Rhoades
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Pharmacology Training Program, Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Veterans Affairs, Nashville VA Medical Center, Tennessee Valley Healthcare System, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
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10
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Ríos Medrano MA, Bigi MM, Martínez Ponce P, Podesta EJ, Orlando UD. Exposure to anticancer drugs modulates the expression of ACSL4 and ABCG2 proteins in adrenocortical carcinoma cells. Heliyon 2023; 9:e20769. [PMID: 37867801 PMCID: PMC10585233 DOI: 10.1016/j.heliyon.2023.e20769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 09/21/2023] [Accepted: 10/05/2023] [Indexed: 10/24/2023] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare and malignant disease, with more than 50 % of patients developing hormone-secreting tumors. These tumors are genetically heterogeneous and potentially lethal, as metastasis is often underway at the time of diagnosis. While chemoresistance can be multifactorial, Acyl CoA synthetase 4 (ACSL4) is known to contribute to the generation of highly aggressive cellular phenotypes, while increased expression and activity of multidrug transporters such as ATP-binding cassette subfamily G member 2 (ABCG2) are known to play a key role. Therefore, the objective of this work was to determine changes in the expression of ACSL4 and ABCG2 in ACC cell lines after exposure to antitumor drugs. Bioinformatics analysis of public database GSE140818 revealed higher ACSL4 and ABCG2 expression in HAC15 cells resistant to mitotane when compared to wild type cells. In addition, our studies revealed an increase in ACSL4 and ABCG2 expression in lowly aggressive H295R cells undergoing early treatment with non-lethal concentrations of mitotane, doxorubicin and cisplatin. Comparable results were obtained in lowly aggressive breast cancer cells MCF-7. The increase in ACSL4 and ABCG2 expression favored tumor cell viability, proliferation and compound efflux, an effect partially offset by ACSL4 and ABCG2 inhibitors. These results provide relevant data on the undesired molecular effects of antitumor drugs and may fuel future studies on patients' early response to antitumor treatment.
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Affiliation(s)
- Mayra Agustina Ríos Medrano
- Universidad de Buenos Aires-CONICET. Instituto de Investigaciones Biomédicas (INBIOMED). Buenos Aires. Argentina
| | - María Mercedes Bigi
- Universidad de Buenos Aires-CONICET. Instituto de Investigaciones Biomédicas (INBIOMED). Buenos Aires. Argentina
| | - Paloma Martínez Ponce
- Universidad de Buenos Aires-CONICET. Instituto de Investigaciones Biomédicas (INBIOMED). Buenos Aires. Argentina
| | - Ernesto Jorge Podesta
- Universidad de Buenos Aires-CONICET. Instituto de Investigaciones Biomédicas (INBIOMED). Buenos Aires. Argentina
- Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Buenos Aires. Argentina
| | - Ulises Daniel Orlando
- Universidad de Buenos Aires-CONICET. Instituto de Investigaciones Biomédicas (INBIOMED). Buenos Aires. Argentina
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11
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Mize BK, Salvi A, Ren Y, Burdette JE, Fuchs JR. Discovery and development of botanical natural products and their analogues as therapeutics for ovarian cancer. Nat Prod Rep 2023; 40:1250-1270. [PMID: 37387219 PMCID: PMC10448539 DOI: 10.1039/d2np00091a] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2023]
Abstract
Covering: 2015 through the end of July 2022Ovarian cancer is one of the most common cancers affecting the female reproductive organs and has the highest mortality rate among gynecological cancers. Although botanical drugs and their derivatives, namely members of the taxane and camptothecin families, represent significant therapeutics currently available for the treatment of ovarian cancer, new drugs that have alternative mechanisms of action are still needed to combat the disease. For this reason, many efforts to identify additional novel compounds from botanical sources, along with the further development of existing therapeutics, have continued to appear in the literature. This review is designed to serve as a comprehensive look at both the currently available small-molecule therapeutic options and the recently reported botanically-derived natural products currently being studied and developed as potential future therapeutics that could one day be used against ovarian cancer. Specifically, key properties, structural features, and biological data are highlighted that are important for the successful development of potential agents. Recently reported examples are specifically discussed in the context of "drug discovery attributes," including the presence of structure-activity relationship, mechanism of action, toxicity, and pharmacokinetic studies, to help indicate the potential for future development and to highlight where these compounds currently exist in the development process. The lessons learned from both the successful development of the taxanes and camptothecins, as well as the strategies currently being employed for new drug development, are expected to ultimately help guide the future development of botanical natural products for ovarian cancer.
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Affiliation(s)
- Brittney K Mize
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
| | - Amrita Salvi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yulin Ren
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
| | - Joanna E Burdette
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | - James R Fuchs
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
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12
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Xia W, Chen W, Ni C, Meng X, Wu J, Yang Q, Tang H, Yuan H, Fang S. Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway. Breast Cancer Res 2023; 25:85. [PMID: 37461019 PMCID: PMC10351125 DOI: 10.1186/s13058-023-01672-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 06/07/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. METHODS The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. RESULTS CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. CONCLUSIONS These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.
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Affiliation(s)
- Wenjie Xia
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Wuzhen Chen
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Ni
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuli Meng
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Jun Wu
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Qiong Yang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Hongchao Tang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Hongjun Yuan
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
| | - Shan Fang
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
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13
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Temesszentandrási-Ambrus C, Nagy G, Bui A, Gáborik Z. A Unique In Vitro Assay to Investigate ABCB4 Transport Function. Int J Mol Sci 2023; 24:ijms24054459. [PMID: 36901890 PMCID: PMC10003010 DOI: 10.3390/ijms24054459] [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: 01/13/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/12/2023] Open
Abstract
ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may lead to cholestasis and drug-induced liver injury (DILI), although compared with other drug transporters, there are only a few identified substrates and inhibitors of ABCB4. Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence with ABCB1, also known to have common drug substrates and inhibitors, we aimed to develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport assays. This in vitro system allows the screening of ABCB4-specific drug substrates and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute a reproducible, conclusive, and easy to use assay to study drug interactions with digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent with prior findings concerning hepatotoxicity causality and provide new insights for identifying drugs as potential ABCB4 inhibitors and substrates.
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Affiliation(s)
- Csilla Temesszentandrási-Ambrus
- SOLVO Biotechnology, Charles River Laboratories Hungary, H-1117 Budapest, Hungary
- Doctoral School of Molecular Medicine, Semmelweis University, Tűzoltó u. 37-47, H-1094 Budapest, Hungary
| | - Gábor Nagy
- SOLVO Biotechnology, Charles River Laboratories Hungary, H-1117 Budapest, Hungary
| | - Annamária Bui
- SOLVO Biotechnology, Charles River Laboratories Hungary, H-1117 Budapest, Hungary
| | - Zsuzsanna Gáborik
- SOLVO Biotechnology, Charles River Laboratories Hungary, H-1117 Budapest, Hungary
- Correspondence: ; Tel.: +36-303879216
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14
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Kinnel B, Singh SK, Oprea-Ilies G, Singh R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers (Basel) 2023; 15:1320. [PMID: 36831661 PMCID: PMC9954028 DOI: 10.3390/cancers15041320] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance.
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Affiliation(s)
- Briana Kinnel
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Gabriela Oprea-Ilies
- Department of Pathology & Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
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15
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Daniel P, Balušíková K, Václavíková R, Šeborová K, Ransdorfová Š, Valeriánová M, Wei L, Jelínek M, Tlapáková T, Fleischer T, Kristensen VN, Souček P, Ojima I, Kovář J. ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines. Genes (Basel) 2023; 14:genes14020296. [PMID: 36833223 PMCID: PMC9957548 DOI: 10.3390/genes14020296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.
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Affiliation(s)
- Petr Daniel
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
| | - Kamila Balušíková
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
| | - Radka Václavíková
- Toxicogenomics Unit, National Institute of Public Health, 100 00 Prague, Czech Republic
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine, Charles University, 323 00 Pilsen, Czech Republic
| | - Karolína Šeborová
- Toxicogenomics Unit, National Institute of Public Health, 100 00 Prague, Czech Republic
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine, Charles University, 323 00 Pilsen, Czech Republic
| | - Šárka Ransdorfová
- Department of Cytogenetics, Institute of Hematology and Blood Transfusion, 128 00 Prague, Czech Republic
| | - Marie Valeriánová
- Department of Cytogenetics, Institute of Hematology and Blood Transfusion, 128 00 Prague, Czech Republic
| | - Longfei Wei
- Department of Chemistry, Institute of Chemical Biology & Drug Discovery, Stony Brook University—State University of New York, Stony Brook, NY 11794, USA
| | - Michael Jelínek
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
| | - Tereza Tlapáková
- Department of Cell Biology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
| | - Thomas Fleischer
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway
| | - Vessela N. Kristensen
- Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway
| | - Pavel Souček
- Toxicogenomics Unit, National Institute of Public Health, 100 00 Prague, Czech Republic
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine, Charles University, 323 00 Pilsen, Czech Republic
| | - Iwao Ojima
- Department of Chemistry, Institute of Chemical Biology & Drug Discovery, Stony Brook University—State University of New York, Stony Brook, NY 11794, USA
| | - Jan Kovář
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
- Correspondence: ; Tel.: +420-267-102-658
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16
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Kumar S, Singh SK, Srivastava P, Suresh S, Rana B, Rana A. Interplay between MAP kinases and tumor microenvironment: Opportunity for immunotherapy in pancreatic cancer. Adv Cancer Res 2023. [PMID: 37268394 DOI: 10.1016/bs.acr.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), commonly called pancreatic cancer, is aggressive cancer usually detected at a late stage, limiting treatment options with modest clinical responses. It is projected that by 2030, PDAC will be the second most common cause of cancer-related mortality in the United States. Drug resistance in PDAC is common and significantly affects patients' overall survival (OS). Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. However, effective drugs directed to target prevalent KRAS mutants in pancreatic cancer are not in clinical practice. Accordingly, efforts are continued on identifying alternative druggable target(s) or approaches to improve patient outcomes with PDAC. In most PDAC cases, the KRAS mutations turn-on the RAF-MEK-MAPK pathways, leading to pancreatic tumorigenesis. The MAPK signaling cascade (MAP4K→MAP3K→MAP2K→MAPK) plays a central role in the pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance. The immunosuppressive pancreatic cancer TME is another unfavorable factor affecting the therapeutic efficacy of chemotherapy and immunotherapy. The immune checkpoint proteins (ICPs), including CTLA-4, PD-1, PD-L1, and PD-L2, are critical players in T cell dysfunction and pancreatic tumor cell growth. Here, we review the activation of MAPKs, a molecular trait of KRAS mutations and their impact on pancreatic cancer TME, chemoresistance, and expression of ICPs that could influence the clinical outcomes in PDAC patients. Therefore, understanding the interplay between MAPK pathways and TME could help to design rational therapy combining immunotherapy and MAPK inhibitors for pancreatic cancer treatment.
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17
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Olaparib Conjugates with Selenopheno[3,2- c]quinolinone Inhibit PARP1 and Reverse ABCB1-Related Multidrug Resistance. Pharmaceutics 2022; 14:pharmaceutics14122571. [PMID: 36559065 PMCID: PMC9783898 DOI: 10.3390/pharmaceutics14122571] [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: 10/01/2022] [Revised: 11/10/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that hampers malignant cell DNA repair could be a powerful tool in anticancer therapy. Herein, we report the design and synthesis of three novel olaparib conjugates with selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells as well as their mechanism of action. It was found that the most potent chemosensitizer among studied compounds preserves PARP1 inhibitory activity and attenuates cells' resistance to doxorubicin by inhibiting ABCB1 transporter activity. These results demonstrate that the conjugation of PARP inhibitors with selenophenoquinolinones is a prospective direction for the development of agents for the treatment of MDR cancers.
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18
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Liu C, Li S, Zhang X, Jin C, Zhao B, Li L, Miao QR, Jin Y, Fan Z. Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway. Cancer Gene Ther 2022; 30:647-658. [PMID: 36241702 DOI: 10.1038/s41417-022-00542-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 09/15/2022] [Accepted: 10/03/2022] [Indexed: 12/29/2022]
Abstract
Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.
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Affiliation(s)
- Chang Liu
- Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Sijie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaoxiao Zhang
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunxiang Jin
- Institute Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Baofeng Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute, Liaoning, China
| | - Liying Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qing Robert Miao
- Department of Foundations of Medicine, NYU Long Island School of Medicine, New York, NY, USA.
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
| | - Zhimin Fan
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
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19
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Wang H, Zhao C, Santa-Maria CA, Emens LA, Popel AS. Dynamics of tumor-associated macrophages in a quantitative systems pharmacology model of immunotherapy in triple-negative breast cancer. iScience 2022; 25:104702. [PMID: 35856032 PMCID: PMC9287616 DOI: 10.1016/j.isci.2022.104702] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/05/2022] [Accepted: 06/27/2022] [Indexed: 11/07/2022] Open
Abstract
Quantitative systems pharmacology (QSP) modeling is an emerging mechanistic computational approach that couples drug pharmacokinetics/pharmacodynamics and the course of disease progression. It has begun to play important roles in drug development for complex diseases such as cancer, including triple-negative breast cancer (TNBC). The combination of the anti-PD-L1 antibody atezolizumab and nab-paclitaxel has shown clinical activity in advanced TNBC with PD-L1-positive tumor-infiltrating immune cells. As tumor-associated macrophages (TAMs) serve as major contributors to the immuno-suppressive tumor microenvironment, we incorporated the dynamics of TAMs into our previously published QSP model to investigate their impact on cancer treatment. We show that through proper calibration, the model captures the macrophage heterogeneity in the tumor microenvironment while maintaining its predictive power of the trial results at the population level. Despite its high mechanistic complexity, the modularized QSP platform can be readily reproduced, expanded for new species of interest, and applied in clinical trial simulation.
A mechanistic model of quantitative systems pharmacology in immuno-oncology Dynamics of tumor-associated macrophages are integrated into our previous work Conducting in silico clinical trials to predict clinical response to cancer therapy
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Affiliation(s)
- Hanwen Wang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Chen Zhao
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu211166, China
| | - Cesar A Santa-Maria
- Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD21205, USA
| | - Leisha A Emens
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD21205, USA
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20
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Rottlerin promotes anti-metastatic events by ameliorating pharmacological parameters of paclitaxel: An in-vivo investigation in the orthotopic mouse model of breast cancer. Chem Biol Interact 2022; 366:110109. [PMID: 35995259 DOI: 10.1016/j.cbi.2022.110109] [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: 06/25/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 02/07/2023]
Abstract
Despite substantial breakthroughs in cancer research, there is hardly any specific therapy available to date that can alleviate triple-negative breast cancer (TNBC). Paclitaxel is the first-line chemotherapy option, but its treatment is often associated with early discontinuation of therapy due to the development of resistance and/or precipitation of severe side effects. In the quest to establish a suitable combination therapy with a low dose of paclitaxel, we explored rottlerin (a pure and characterized phytoconstituent from Mallotus philippensis) because of its multifaceted pharmacological actions against cancer. The study was performed to assess the therapeutic effects of rottlerin (5-20 mg/kg) with a low dose of paclitaxel (5 mg/kg) using a highly aggressive mouse mammary carcinoma model. Rottlerin augmented the paclitaxel effect by reducing tumor burden as well as metastatic lung nodules formation. Rottlerin in combination with paclitaxel remarkably altered the expression of vital epithelial-mesenchymal transition (EMT) markers such as E-cadherin, Snail 1, & Vimentin and thus improved the anti-metastatic efficacy of paclitaxel. Significant attenuation of anti-apoptotic protein (Bcl-2) along with amplification of pro-apoptotic (cleaved PARP) marker confers that rottlerin could ameliorate the pro-apoptotic potential of paclitaxel. In this study, a rational combination of rottlerin and paclitaxel treatment curtailed CYP2J2 expression and epoxyeicosatrienoic acids (EETs) levels, responsible for restrain tumor growth and metastasis. Additionally, rottlerin lessened paclitaxel treatment-mediated hematological alterations and prevented paclitaxel treatment-linked key serum biochemical changes related to organ toxicities. These rottlerin treatment-mediated protective changes are closely associated with the lower paclitaxel accumulation in the corresponding tissues. Rottlerin caused significant pharmacokinetic interaction with paclitaxel to boost the plasma level of paclitaxel in a typical mouse model and possibly helpful towards the use of a low dose of paclitaxel in combination. Overall, it can be stated that rottlerin has significant potential to augment the anti-metastatic efficacy of paclitaxel via impeding EMT activation along with attenuating its treatment-associated toxicological alterations. Hence, rottlerin has significant potential to explore further as a suitable neoadjuvant therapy with paclitaxel against TNBC.
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Wu ZL, Chen Y, Qu Z, Wu GY, He XF, Huang JW, Meng QQ, Hu YH, Shen XL, Yang RY, Hu YJ. An ester derivative of tenacigenin B from Marsdenia tenacissima (Roxb.) Wight et Arn reversed paclitaxel-induced MDR in vitro and in vivo by inhibiting both P-gp and MRP2. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115353. [PMID: 35533911 DOI: 10.1016/j.jep.2022.115353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/29/2022] [Accepted: 05/03/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Marsdenia tenacissima is a medicinal plant, used as a raw material for cancer treatment in China. In our previous studies, 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2), the main steroid aglycone isolated from M. tenacissima, was found to significantly enhance the antitumor activity of paclitaxel (PTX) in vivo. However, it is unclear whether MT2 reverses multidrug resistance (MDR) in tumors. AIM OF THE STUDY To determine the role and mechanism of MT2 in reversing tumor MDR. MATERIALS AND METHODS MDR cell line HeLa/Tax was established from the human cervical carcinoma cell line HeLa by long-term exposure to subtoxic concentrations of PTX and was used to evaluate the ability of MT2 to restore chemosensitivity of cells both in vitro and in a nude mouse model. The expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) was determined using western blotting and immunohistochemistry. The substrate transport function was assessed using an MDR function assay kit. The binding modes of MT2 and P-gp were determined using the conformation-sensitive anti-P-gp antibodies. The permeability and transport properties of MT2 were analyzed in Caco-2 cell monolayers. RESULTS Compared to parental cells, HeLa/Tax cells overexpress P-gp and MRP2 and are approximately 100-360 fold more resistant to the anticancer drugs PTX, docetaxel, and vinblastine. MT2 at 5 or 10 μmol/L significantly increased the sensitivity of HeLa/Tax to these three anticancer drugs (18-56-fold decrease in IC50 value) and suppressed the expression of P-gp and MRP2. Knockdown of P-gp with small interfering RNA partially reversed MT2-induced sensitivity to PTX in HeLa/Tax cells. Moreover, MT2 directly inhibited P-gp-mediated substrate transport while interacting with membrane P-gp in non-substrate ways. MT2 was highly permeable and could not be transported in the Caco-2 cell monolayers. In nude mice bearing HeLa/Tax xenografts, the combination treatment with MT2 and PTX exerted a synergistic inhibitory effect on the growth of tumors and the expression of P-gp and MRP2 without increasing toxicity. CONCLUSION MT2 is a potential agent for reversing MDR. It impedes membrane drug efflux pumps by suppressing P-gp and MRP2 expression, and directly inhibiting the transport function of P-gp.
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Affiliation(s)
- Zhou-Li Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Yan Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Zhao Qu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Gui-Yun Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Xiao-Feng He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Jia-Wen Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Qi-Qi Meng
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Yuan-Hao Hu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Xiao-Ling Shen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Rui-Yi Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Ying-Jie Hu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
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22
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Andres AE, Mariano A, Rane D, Peterson BR. Quantification of Engagement of Microtubules by Small Molecules in Living Cells by Flow Cytometry. ACS BIO & MED CHEM AU 2022; 2:529-537. [PMID: 36281300 PMCID: PMC9585582 DOI: 10.1021/acsbiomedchemau.2c00031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/29/2022]
Abstract
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Drugs such as paclitaxel (Taxol) that bind microtubules
are widely
used for the treatment of cancer. Measurements of the affinity and
selectivity of these compounds for their targets are largely based
on studies of purified proteins, and only a few quantitative methods
for the analysis of interactions of small molecules with microtubules
in living cells have been reported. We describe here a novel method
for rapidly quantifying the affinities of compounds that bind polymerized
tubulin in living HeLa cells. This method uses the fluorescent molecular
probe Pacific Blue-GABA-Taxol in conjunction with verapamil to block
cellular efflux. Under physiologically relevant conditions of 37 °C,
this combination allowed quantification of equilibrium saturation
binding of this probe to cellular microtubules (Kd = 1.7 μM) using flow cytometry. Competitive binding
of the microtubule stabilizers paclitaxel (cellular Ki = 22 nM), docetaxel (cellular Ki = 16 nM), cabazitaxel (cellular Ki = 6 nM), and ixabepilone (cellular Ki = 10 nM) revealed intracellular affinities for microtubules that
closely matched previously reported biochemical affinities. By including
a cooperativity factor (α) for curve fitting of allosteric modulators,
this probe also allowed quantification of binding (Kb) of the microtubule destabilizers colchicine (Kb = 80 nM, α = 0.08), vinblastine (Kb = 7 nM, α = 0.18), and maytansine (Kb = 3 nM, α = 0.21). Screening of this
assay against 1008 NCI diversity compounds identified NSC 93427 as
a novel microtubule destabilizer (Kb =
485 nM, α = 0.02), illustrating the potential of this approach
for drug discovery.
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Affiliation(s)
- Angelo E. Andres
- Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Andres Mariano
- Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Digamber Rane
- Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Blake R. Peterson
- Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
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Alsayadi AI, Abutaha N, Almutairi BO, Al-Mekhlafi FA, Wadaan MA. Evaluating the efficacy of an innovative herbal formulation (HF6) on different human cancer cell lines. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:51768-51777. [PMID: 35249198 DOI: 10.1007/s11356-022-19529-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/25/2022] [Indexed: 06/14/2023]
Abstract
Cancer is reported to be the leading cause of death and illness worldwide. This research aims to evaluate the phytochemicals, antioxidant, cytotoxic, and apoptotic activities of the polyherbal formulation HF6. HF6 was prepared by blending equal quantities of plants powder, namely, Curcuma longa, Salvia officinalis, Cinnamomum zeylanicum, Capsicum annuum, Zingiber officinale, and Syzygium aromaticum, and later extracted using hexane (HF6H), chloroform (HF6C), ethyl acetate (HF6E), and methanol (HF6M) in Soxhlet apparatus. Among the four different extracts, only the hexane extract (HF6H) was significantly effective. The HF6H extract showed antioxidant and anticancer potentials against different cancer cell lines, and moderate cytotoxicity against non-cancer cells, rendering it a promising remedy. In addition, it exerted tremendous cytotoxic effects on MCF-7, Huh-7, HCT116, MDA-MB-231, LoVo, and HepG2 cells with IC50 values of 2.02, 4.5, 6.9, 11.4, 23.5, and 34.7 µg/mL, respectively. The morphological hallmarks of apoptosis such as the rounding of cells, loss of contact with neighboring cells, formation of cell membrane blebbing, and microspike protrusion were detected using several different techniques. DAPI staining revealed apoptotic nuclear morphology such as condensation and DNA fragmentation. The morphological changes of MCF7 cells were also analyzed by AO/EB fluorescence staining. MCF7-stained green cells were viable cells, whereas the treated cells showed fragmented green nuclei representing early apoptosis. The phytochemical screening of HF6H showed positive results regarding the presence of alkaloids, polyphenols, flavonoids, and sterols. The GC-MS (gas chromatography-mass spectrometry) analysis of the HF6H extract indicated the presence of 12 compounds, mainly trans-caryophyllene (21.55%), cis-isoeugenol (18.42%), acetyleugenol (17.53%), alpha farnesene (10.0%), and zingiberene (8.55%). However, further investigation could be carried out to examine the toxicity of the extract on animal models.
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Affiliation(s)
- Ahmed I Alsayadi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Nael Abutaha
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
| | - Bader O Almutairi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Fahd A Al-Mekhlafi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Mohamed A Wadaan
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
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Español A, Sanchez Y, Salem A, Obregon J, Sales ME. Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells. World J Clin Oncol 2022; 13:505-519. [PMID: 35949430 PMCID: PMC9244968 DOI: 10.5306/wjco.v13.i6.505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/24/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.
AIM To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.
METHODS Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.
RESULTS Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.
CONCLUSION Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.
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Affiliation(s)
- Alejandro Español
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Yamila Sanchez
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Agustina Salem
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Jaqueline Obregon
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Maria Elena Sales
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
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25
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Pitchika S, Sahoo SK. Paclitaxel and Lapatinib dual loaded chitosan-coated PLGA nanoparticles enhance cytotoxicity by circumventing MDR1-mediated trastuzumab resistance in HER2 positive breast cancers: In-vitro and in-vivo studies. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Dobiasová S, Szemerédi N, Kučerová D, Koucká K, Václavíková R, Gbelcová H, Ruml T, Domínguez-Álvarez E, Spengler G, Viktorová J. Ketone-selenoesters as potential anticancer and multidrug resistance modulation agents in 2D and 3D ovarian and breast cancer in vitro models. Sci Rep 2022; 12:6548. [PMID: 35449387 PMCID: PMC9023544 DOI: 10.1038/s41598-022-10311-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/11/2022] [Indexed: 12/13/2022] Open
Abstract
Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.
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Affiliation(s)
- Simona Dobiasová
- Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 3, 166 28, Prague 6, Czechia
| | - Nikoletta Szemerédi
- Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6725, Hungary
| | - Denisa Kučerová
- Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 3, 166 28, Prague 6, Czechia
| | - Kamila Koucká
- Toxicogenomics Unit, National Institute of Public Health, Šrobárova 49, 100 00, Prague, Czechia.,Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00, Pilsen, Czechia
| | - Radka Václavíková
- Toxicogenomics Unit, National Institute of Public Health, Šrobárova 49, 100 00, Prague, Czechia.,Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00, Pilsen, Czechia
| | - Helena Gbelcová
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia
| | - Tomáš Ruml
- Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 3, 166 28, Prague 6, Czechia
| | - Enrique Domínguez-Álvarez
- Instituto de Química Orgánica General (IQOG-CSIC), Consejo Superior de Investigaciones Científicas, Juan de la Cierva 3, 28006, Madrid, Spain.
| | - Gabriella Spengler
- Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6725, Hungary.
| | - Jitka Viktorová
- Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 3, 166 28, Prague 6, Czechia.
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27
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Maiuolo J, Musolino V, Gliozzi M, Carresi C, Oppedisano F, Nucera S, Scarano F, Scicchitano M, Guarnieri L, Bosco F, Macrì R, Ruga S, Cardamone A, Coppoletta AR, Ilari S, Mollace A, Muscoli C, Cognetti F, Mollace V. The Employment of Genera Vaccinium, Citrus, Olea, and Cynara Polyphenols for the Reduction of Selected Anti-Cancer Drug Side Effects. Nutrients 2022; 14:1574. [PMID: 35458136 PMCID: PMC9025632 DOI: 10.3390/nu14081574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/02/2022] [Accepted: 04/08/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer is one of the most widespread diseases globally and one of the leading causes of death. Known cancer treatments are chemotherapy, surgery, radiation therapy, targeted hormonal therapy, or a combination of these methods. Antitumor drugs, with different mechanisms, interfere with cancer growth by destroying cancer cells. However, anticancer drugs are dangerous, as they significantly affect both cancer cells and healthy cells. In addition, there may be the onset of systemic side effects perceived and mutagenicity, teratogenicity, and further carcinogenicity. Many polyphenolic extracts, taken on top of common anti-tumor drugs, can participate in the anti-proliferative effect of drugs and significantly reduce the side effects developed. This review aims to discuss the current scientific knowledge of the protective effects of polyphenols of the genera Vaccinium, Citrus, Olea, and Cynara on the side effects induced by four known chemotherapy, Cisplatin, Doxorubicin, Tamoxifen, and Paclitaxel. In particular, the summarized data will help to understand whether polyphenols can be used as adjuvants in cancer therapy, although further clinical trials will provide crucial information.
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Affiliation(s)
- Jessica Maiuolo
- Laboratoy of Pharmaceutical Biology, IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Campus Universitario di Germaneto, 88100 Canzaro, Italy;
| | - Vincenzo Musolino
- Laboratoy of Pharmaceutical Biology, IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Campus Universitario di Germaneto, 88100 Canzaro, Italy;
| | - Micaela Gliozzi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Cristina Carresi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Francesca Oppedisano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Saverio Nucera
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Federica Scarano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Miriam Scicchitano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Lorenza Guarnieri
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Francesca Bosco
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Roberta Macrì
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Stefano Ruga
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Antonio Cardamone
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Anna Rita Coppoletta
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Sara Ilari
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Annachiara Mollace
- Medical Oncology 1, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy; (A.M.); (F.C.)
| | - Carolina Muscoli
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
| | - Francesco Cognetti
- Medical Oncology 1, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy; (A.M.); (F.C.)
| | - Vincenzo Mollace
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.G.); (C.C.); (F.O.); (S.N.); (F.S.); (M.S.); (L.G.); (F.B.); (R.M.); (S.R.); (A.C.); (A.R.C.); (S.I.); (V.M.)
- IRCCS San Raffaele, Via di Valcannuta 247, 00133 Rome, Italy
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FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3032590. [PMID: 35141332 PMCID: PMC8820921 DOI: 10.1155/2022/3032590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/19/2021] [Accepted: 01/12/2022] [Indexed: 11/25/2022]
Abstract
Objective The aim of the present study was to investigate the effect of forkhead box M1 (FOXM1) to paclitaxel resistance in cervical cancer cells, to determine the underlying mechanism, and to identify novel targets for the treatment of paclitaxel-resistant cervical cancer. Methods Paclitaxel-resistant Caski cells (Caski/Taxol cells) were established by intermittently exposing the Caski cells to gradually increasing concentrations of paclitaxel. The association between FOXM1, ATP-binding cassette subfamily C member 5 (ABCC5), and cervical cancer cell drug resistance was assessed by overexpressing or knocking down the expression of FOXM1 in Caski or Caski/Taxol cells. The protein and mRNA expression levels, the ratio of cellular apoptosis, and cell migration as well as intracellular drug concentrations were measured in cells following the different treatments. Results After the successful establishment of resistant Caski/Taxol cells, cell cycle distribution analysis showed that a significantly larger percentage of Caski/Taxol cells was in the G0/G1 stage compared with the Caski cells (P < 0.01), whereas a significantly larger percentage of Caski cells was in the S and G2/M stage compared with the Caski/Taxol cells following treatment with paclitaxel (P < 0.01). Both the protein and mRNA expression levels of FOXM1 and ABCC5 transporters were significantly higher in the paclitaxel-resistant Caski/Taxol cells compared with Caski cells (P < 0.05). Knockdown of FOXM1 significantly lowered the protein expression levels of FOXM1 and ABCC5. Intracellular paclitaxel concentrations were significantly higher amongst the Caski/Taxol cells following the knockdown of FOXM1 by shRNA or Siomycin A (P < 0.05). Conclusion FOXM1 promotes drug resistance in cervical cancer cells by regulating ABCC5 gene transcription. The knockdown of FOXM1 with shRNA or Siomycin A promotes paclitaxel-induced cell death by regulating ABCC5 gene transcription.
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Esparza-López J, Longoria O, De La Cruz-Escobar EN, Garibay-Díaz JC, León-Rodríguez E, De Jesús Ibarra-Sánchez M. Paclitaxel resistance is mediated by NF-κB on mesenchymal primary breast cancer cells. Oncol Lett 2022; 23:50. [PMID: 34992683 PMCID: PMC8721864 DOI: 10.3892/ol.2021.13168] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/09/2021] [Indexed: 12/16/2022] Open
Abstract
Paclitaxel has been used widely to treat breast cancer and other types of cancer. However, resistance is a major cause of failure for treatment and results in cancer progression. The present study investigated the association between paclitaxel resistance and the mesenchymal phenotype, using a model of primary breast cancer cells and employing four different cultures, two with an epithelial phenotype (MBCDF and MBCD17) and two with a mesenchymal phenotype (MBCDF-D5 and MBCD3). Epithelial-mesenchymal markers were evaluated by western blotting; MBCDF and MBCD17 cells expressed E-cadherin, SNAIL, Slug, and Twist, low levels of N-cadherin, but not vimentin. MBCDF-D5 and MBCD3 cells expressed N-cadherin, vimentin, and higher levels of SNAIL, and low levels of E-cadherin, Slug, and Twist. Cell viability was evaluated using a crystal violet assay after paclitaxel treatment; primary breast cancer cells with mesenchymal phenotype were resistant to paclitaxel compared with the epithelial primary breast cancer cells. Furthermore, using western blotting, it was revealed that mesenchymal cells had elevated levels of nuclear factor-κΒ (NF-κB) p65 and IκB kinase (IKK). Additionally, it was demonstrated that paclitaxel-induced degradation of the inhibitor of NF-κB, activation of NF-κB in a dose-dependent manner, and Bcl-2 and Bcl-xL upregulation. Finally, employing western blotting and crystal violet assays, the effects of the proteasome inhibitor ALLN were assessed. ALLN inhibited paclitaxel-induced NF-κB activation and restored the sensitivity to paclitaxel. Together, these data suggest that targeting the NF-κB/IKK axis might be a promising strategy to overcome paclitaxel resistance.
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Affiliation(s)
- José Esparza-López
- Biochemistry Unit, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico.,Research Support Network, National Autonomous University of Mexico-Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico
| | - Ossian Longoria
- Hematology and Oncology Department, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico
| | | | - Julio Cesar Garibay-Díaz
- Hematology and Oncology Department, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico
| | - Eucario León-Rodríguez
- Hematology and Oncology Department, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico
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Abstract
Taxoids such as paclitaxel (Taxol) are an important class of anticancer drugs that bind β-tubulin and stabilize cellular microtubules. To provide new chemical tools for studies of microtubules, we synthesized derivatives of paclitaxel modified at the 7-position with the small coumarin-derived fluorophore Pacific Blue (PB). Three of these Pacific Blue-Taxoids termed PB-Gly-Taxol, PB-β-Ala-Taxol, and PB-GABA-Taxol bind purified crosslinked microtubules with affinities of 34-265 nM, where the affinity can be tuned based on the length of an amino acid linker. When added to living cells in the presence of verapamil or probenecid as inhibitors of efflux, these compounds allow visualization of the microtubule network by confocal microscopy. We describe methods for the synthesis of these probes, determination of their affinities for crosslinked tubulin, and imaging of microtubules in living HeLa cells. We further describe their uptake by Caco-2 cells and two transporter-deficient Caco-2 knockout cell lines in the absence and presence of efflux inhibitors by flow cytometry. These studies revealed that p-glycoprotein (MDR1) and multidrug-resistance protein 2 (MRP2) are major mediators of efflux of these molecular probes. These compounds provide useful tools for studies of microtubules and cellular efflux transporters in living cells.
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Affiliation(s)
- Angelo E Andres
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Digamber Rane
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Blake R Peterson
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
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The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes. Int J Mol Sci 2021; 23:ijms23010073. [PMID: 35008510 PMCID: PMC8744980 DOI: 10.3390/ijms23010073] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/18/2021] [Accepted: 12/19/2021] [Indexed: 02/07/2023] Open
Abstract
The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.
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Zhao D, Hu C, Fu Q, Lv H. Combined chemotherapy for triple negative breast cancer treatment by paclitaxel and niclosamide nanocrystals loaded thermosensitive hydrogel. Eur J Pharm Sci 2021; 167:105992. [PMID: 34517104 DOI: 10.1016/j.ejps.2021.105992] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/03/2021] [Accepted: 09/05/2021] [Indexed: 11/19/2022]
Abstract
Triple negative breast cancer (TNBC) is the most dangerous subtype of breast cancer accompanying by unfavorable prognosis due to lack of specific therapeutic targets. Paclitaxel (PTX) is the first-line chemotherapeutic drug for TNBC and niclosamide (NLM) was identified as an inhibitor for TNBC and breast cancer stem cells (BCSCs). Intratumoral drug delivery system was a hopeful alternative for chemotherapeutic drug administration due to its targeting efficiency with lower systemic toxicity. Herein, an injectable PTX nanocrystals (PTX-NCs) and NLM nanocrystals (NLM-NCs) co-loaded PLGA-PEG-PLGA thermosensitive hydrogel (PNNCs-Ts Gel) was designed for TNBC intratumoral treatment. The final formulation realized high drug loading and appropriate particle size. PNNCs-Ts Gel displayed sustained drug release for up to 8 days in vitro. In vitro antitumor tests observed synergetic effects of combined therapy in terms of inhibiting cell proliferation and migration, inducing apoptosis. In vivo combined therapy presented a tumor growth inhibition rate about 68.8% and desired safety. Moreover, tumors after PNNCs-Ts Gel intratumoral injection possessed the lowest ratio of BCSCs, exhibiting this formulation had good ability in suppressing BCSCs and therefore could possibly prevent TNBC recurrence and metastasis. These results suggested that PNNCs-Ts Gel could be a promising strategy for TNBC treatment.
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Affiliation(s)
- Deqian Zhao
- Beijing Leadingpharm Medical technology development Co. Ltd, Beijing 100094, China
| | - Chenlu Hu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211198, China
| | - Qiang Fu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211198, China.
| | - Huixia Lv
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211198, China.
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Wordeman L, Vicente JJ. Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles. Cancers (Basel) 2021; 13:5650. [PMID: 34830812 PMCID: PMC8616087 DOI: 10.3390/cancers13225650] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.
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Affiliation(s)
| | - Juan Jesus Vicente
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA;
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Jiang W, Cai G, Hu P, Wang Y. Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer. Acta Pharm Sin B 2021; 11:3406-3416. [PMID: 34900526 PMCID: PMC8642451 DOI: 10.1016/j.apsb.2021.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022] Open
Abstract
Non-small cell lung cancer is recognized as the deadliest cancer across the globe. In some areas, it is more common in women than even breast and cervical cancer. Its rise, vaulted by smoking habits and increasing air pollution, has garnered much attention and resource in the medical field. The first lung cancer treatments were developed more than half a century ago. Unfortunately, many of the earlier chemotherapies often did more harm than good, especially when they were used to treat genetically unsuitable patients. With the introduction of personalized medicine, physicians are increasingly aware of when, how, and in whom, to use certain anti-cancer agents. Drugs such as tyrosine kinase inhibitors, anaplastic lymphoma kinase inhibitors, and monoclonal antibodies possess limited utility because they target specific oncogenic mutations, but other drugs that target mechanisms universal to all cancers do not. In this review, we discuss many of these non-oncogene-targeting anti-cancer agents including DNA replication inhibitors (i.e., alkylating agents and topoisomerase inhibitors) and cytoskeletal function inhibitors to highlight their application in the setting of personalized medicine as well as their limitations and resistance factors.
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Affiliation(s)
| | - Guiqing Cai
- Quest Diagnostics, San Juan Capistrano, CA 92675, USA
| | - Peter Hu
- The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yue Wang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Víglaš J, Dobiasová S, Viktorová J, Ruml T, Repiská V, Olejníková P, Gbelcová H. Peptaibol-Containing Extracts of Trichoderma atroviride and the Fight against Resistant Microorganisms and Cancer Cells. Molecules 2021; 26:molecules26196025. [PMID: 34641569 PMCID: PMC8512731 DOI: 10.3390/molecules26196025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/26/2021] [Accepted: 09/29/2021] [Indexed: 11/16/2022] Open
Abstract
Fighting resistance to antibiotics and chemotherapeutics has brought bioactive peptides to the fore. Peptaibols are short α-aminoisobutyric acid-containing peptides produced by Trichoderma species. Here, we studied the production of peptaibols by Trichoderma atroviride O1 and evaluated their antibacterial and anticancer activity against drug-sensitive and multidrug-resistant bacterium and cancer cell lines. This was substantiated by an analysis of the activity of the peptaibol synthetase-encoding gene. Atroviridins, 20-residue peptaibols were detected using MALDI-TOF mass spectrometry. Gram-positive bacteria were susceptible to peptaibol-containing extracts of T. atroviride O1. A synergic effect of extract constituents was possible, and the biolo-gical activity of extracts was pronounced in/after the peak of peptaibol synthetase activity. The growth of methicillin-resistant Staphylococcus aureus was reduced to just under 10% compared to the control. The effect of peptaibol-containing extracts was strongly modulated by the lipoteichoic acid and only slightly by the horse blood serum present in the cultivation medium. Peptaibol-containing extracts affected the proliferation of human breast cancer and human ovarian cancer cell lines in a 2D model, including the multidrug-resistant sublines. The peptaibols influenced the size and compactness of the cell lines in a 3D model. Our findings indicate the molecular basis of peptaibol production in T. atroviride O1 and the potential of its peptaibol-containing extracts as antimicrobial/anticancer agents.
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Affiliation(s)
- Ján Víglaš
- Institute of Biochemistry and Microbiology, Faculty of Food and Chemical Technology, Slovak University of Technology in Bratislava, 812 37 Bratislava, Slovakia;
- Correspondence:
| | - Simona Dobiasová
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic; (S.D.); (J.V.); (T.R.)
| | - Jitka Viktorová
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic; (S.D.); (J.V.); (T.R.)
| | - Tomáš Ruml
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic; (S.D.); (J.V.); (T.R.)
| | - Vanda Repiská
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia; (V.R.); (H.G.)
| | - Petra Olejníková
- Institute of Biochemistry and Microbiology, Faculty of Food and Chemical Technology, Slovak University of Technology in Bratislava, 812 37 Bratislava, Slovakia;
| | - Helena Gbelcová
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia; (V.R.); (H.G.)
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Li Y, Inglese M, Dubash S, Barnes C, Brickute D, Braga MC, Wang N, Beckley A, Heinzmann K, Allott L, Lu H, Chen C, Fu R, Carroll L, Aboagye EO. Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics. Pharmaceutics 2021; 13:1246. [PMID: 34452207 PMCID: PMC8400349 DOI: 10.3390/pharmaceutics13081246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18F]-D4-FCH and [18F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics.
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Affiliation(s)
- Yunqing Li
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Marianna Inglese
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Suraiya Dubash
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Chris Barnes
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Diana Brickute
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Marta Costa Braga
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Ning Wang
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Alice Beckley
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Kathrin Heinzmann
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Louis Allott
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Haonan Lu
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Cen Chen
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Ruisi Fu
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
| | - Laurence Carroll
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Eric O. Aboagye
- Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK; (Y.L.); (M.I.); (S.D.); (C.B.); (D.B.); (M.C.B.); (N.W.); (A.B.); (K.H.); (L.A.); (H.L.); (C.C.); (R.F.); (L.C.)
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Du W, Liu X, Yang M, Wang W, Sun J. The Regulatory Role of PRRX1 in Cancer Epithelial-Mesenchymal Transition. Onco Targets Ther 2021; 14:4223-4229. [PMID: 34295164 PMCID: PMC8291965 DOI: 10.2147/ott.s316102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/23/2021] [Indexed: 01/26/2023] Open
Abstract
PRRX1 (paired related homeobox 1), a member of the paired homeobox family, exhibits an important role in tumor. It is closely correlated to the occurrence of epithelial-mesenchymal transition (EMT). PRRX1 is an important transcription factor regulating EMT and plays an important role in tumor progression. In the process of tumor metastasis, PRRX1 mainly regulates the occurrence of EMT in tumor cells through TGF-β signaling pathway, Wnt/β-catenin signaling pathway and Notch signaling pathway. PRRX1 is not only closely related to the tumor cell stemness but also involved in miRNA regulation of EMT. Therefore, PRRX1 may be a target for inhibiting the proliferation, metastasis and stemness of tumor cells. The current review provides a systemic profile of the regulatory role of PRRX1 in cancer epithelial-mesenchymal transition.
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Affiliation(s)
- Wenjiao Du
- Institute of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, Jiangsu, 215009, People's Republic of China
| | - Xinchang Liu
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China
| | - Jing Sun
- Institute of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, Jiangsu, 215009, People's Republic of China
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Huang Y, Zheng Y, Shao X, Shi L, Li G, Huang P. Long non-coding RNA TPT1-AS1 sensitizes breast cancer cell to paclitaxel and inhibits cell proliferation by miR-3156-5p/caspase 2 axis. Hum Cell 2021; 34:1244-1254. [PMID: 33999360 DOI: 10.1007/s13577-021-00541-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022]
Abstract
Long non-coding RNAs (lncRNAs) are key modulators during cancer progression. Application of using lncRNA expression to evaluate patient prognosis and sensitivity to treatment is highly anticipated, yet the expression and mechanism of many lncRNAs remain unknown. Herein, we projected for the investigation of TPT1-AS1 function in breast cancer. TPT1-AS1 was assessed by bioinformatic analysis of publicly available datasets and quantitative real-time PCR (qRT-PCR). Cell sensitivity to paclitaxel and cell proliferation was measured by flow cytometry and CCK-8. Interaction among TPT1-AS1, microRNA (miRNA, miR)-3156-5p and Caspase 2 (CASP2) was studied by bioinformatic analysis, qRT-PCR, western blot as well as dual luciferase reporter assay. Herein, TPT1-AS1 was significantly diminished in breast cancer from publicly available datasets and our collected samples. In breast cancer cells, TPT1-AS1 overexpression repressed cell proliferation and sensitized breast cancer cells to paclitaxel. RegRNA 2.0 predicted a potential interaction between TPT1-AS1 and miR-3156-5p which was confirmed by qRT-PCR as well as dual luciferase reporter assay. CASP2, a proapoptotic gene, was corroborated to be targeted by miR-3156-5p. Meanwhile, TPT1-AS1 upregulated CASP2 in breast cancer cells, and its biological function was reversed by CASP2 knockdown. Collectively, TPT1-AS1 diminished cell proliferation and sensitized cells to chemotherapy by sponging miR-3156-5p and upregulating CASP2, acting as a biomarker for patients with breast cancer.
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Affiliation(s)
- Yuan Huang
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China
| | - Yabing Zheng
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China.
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China.
| | - Xiying Shao
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China
| | - Lei Shi
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China
| | - Guangliang Li
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China
| | - Ping Huang
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang, 310022, People's Republic of China
- Department of Breast Medical Oncology, Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People's Republic of China
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Cao L, Zhou Y, Li X, Lin S, Tan Z, Guan F. Integrating transcriptomics, proteomics, glycomics and glycoproteomics to characterize paclitaxel resistance in breast cancer cells. J Proteomics 2021; 243:104266. [PMID: 34000456 DOI: 10.1016/j.jprot.2021.104266] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/24/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022]
Abstract
Chemoresistance is a major factor driving breast cancer (BC) relapse and the high rates of cancer-related deaths. Aberrant levels of glycans are closely correlated with chemoresistance. The essential functions of glycans in chemoresistance is not systematically studied. In this study, an integrated strategy with a combination of transcriptomics, proteomics, glycomics and glycoproteomics was applied to explore the dysregulation of glycogenes, glycan structures and glycoproteins in chemoresistance of breast cancer cells. In paclitaxel (PTX) resistant MCF7 cells, 19 differentially expressed N-glycan-related proteins were identified, of which MGAT4A was the most significantly down-regulated, consistent with decrease in MGAT4A expression at mRNA level in PTX treated BC cells. Glycomic analysis consistently revealed suppressed levels of multi-antennary branching structures using MALDI-TOF/TOF-MS and lectin microarray. Several target glycoproteins bearing suppressed levels of multi-antennary branching structures were identified, and ERK signaling pathway was strongly suppressed in PTX resistant MCF7 cells. Our findings demonstrated the aberrant levels of multi-antennary branching structures and their target glycoproteins on PTX resistance. Systematically integrative multi-omic analysis is expected to facilitate the discovery of the aberrant glycosyltransferases, N-glycosylation and glycoproteins in tumor progression and chemoresistance. SIGNIFICANCE: An integrated strategy with a combination of transcriptomics, proteomics, glycomics and glycoproteomics is crucial to understand the association between glycans and chemoresistance in BC. In this multi-omic analysis, we identified unique glycan-related protein, glycan and glycoprotein signatures defining PTX chemoresistance in BC. This study might provide valuable information to understand molecular mechanisms underlying chemoresistance in BC.
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Affiliation(s)
- Lin Cao
- International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an 710069, PR China
| | - Yue Zhou
- International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an 710069, PR China; The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an 710069, PR China
| | - Shuai Lin
- Department of Oncology, The second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zengqi Tan
- International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an 710069, PR China
| | - Feng Guan
- International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an 710069, PR China.
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Grigoreva T, Sagaidak A, Romanova A, Novikova D, Garabadzhiu A, Tribulovich V. Establishment of drug-resistant cell lines under the treatment with chemicals acting through different mechanisms. Chem Biol Interact 2021; 344:109510. [PMID: 33974899 DOI: 10.1016/j.cbi.2021.109510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/28/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023]
Abstract
The problem of chemoresistance development is an inescapable flipside of modern oncotherapy, in particular for сolorectal cancer patients. The search for or development of drugs effective against resistant tumors involves the use of model resistant cell lines in vitro. To obtain such lines, we reproduced the development of chemoresistance of human colon adenocarcinoma cells under the treatment with drugs of different mechanisms, a cytostatic (paclitaxel) and a targeted agent (Nutlin-3a, an inhibitor of p53-Mdm2 protein-protein interaction). In each case, we gradually increased the content of the substance in the medium, starting from effective concentrations that do not cause total cell death. When studying the lines resistant to the corresponding drug, we noted a reduced sensitivity to the drug of another mechanism of action. Analysis of the original and resistant lines showed that the cells use the universal efflux defense mechanism. The observed effect can be partially neutralized using inhibitors of the ABC transport proteins, including P-glycoprotein, known for its oncoprotective function. The role of the latter was confirmed by real-time RT-PCR and Western blotting.
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Affiliation(s)
- Tatyana Grigoreva
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia.
| | - Aleksandra Sagaidak
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia
| | - Angelina Romanova
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia
| | - Daria Novikova
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia
| | - Aleksander Garabadzhiu
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia
| | - Viacheslav Tribulovich
- St. Petersburg State Institute of Technology (Technical University), Moskovskii Prospect, 26, St. Petersburg, 190013, Russia
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Pleiotropic Roles of ABC Transporters in Breast Cancer. Int J Mol Sci 2021; 22:ijms22063199. [PMID: 33801148 PMCID: PMC8004140 DOI: 10.3390/ijms22063199] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/16/2022] Open
Abstract
Chemotherapeutics are the mainstay treatment for metastatic breast cancers. However, the chemotherapeutic failure caused by multidrug resistance (MDR) remains a pivotal obstacle to effective chemotherapies of breast cancer. Although in vitro evidence suggests that the overexpression of ATP-Binding Cassette (ABC) transporters confers resistance to cytotoxic and molecularly targeted chemotherapies by reducing the intracellular accumulation of active moieties, the clinical trials that target ABCB1 to reverse drug resistance have been disappointing. Nevertheless, studies indicate that ABC transporters may contribute to breast cancer development and metastasis independent of their efflux function. A broader and more clarified understanding of the functions and roles of ABC transporters in breast cancer biology will potentially contribute to stratifying patients for precision regimens and promote the development of novel therapies. Herein, we summarise the current knowledge relating to the mechanisms, functions and regulations of ABC transporters, with a focus on the roles of ABC transporters in breast cancer chemoresistance, progression and metastasis.
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Zajdel A, Wilczok A, Jelonek K, Kaps A, Musiał-Kulik M, Kasperczyk J. Cytotoxic effect of targeted biodegradable epothilone B and rapamycin co-loaded nanocarriers on breast cancer cells. J Biomed Mater Res A 2021; 109:1693-1700. [PMID: 33719211 DOI: 10.1002/jbm.a.37164] [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: 10/07/2020] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 12/23/2022]
Abstract
The new therapeutic solutions for breast cancer treatment are needed, for example, combined therapy consisted of several drugs that characterize different mechanisms of action and modern drug delivery systems. Therefore, we used combination of epothilone B (EpoB) and rapamycin (Rap) to analyze the cytotoxic effect against breast cancer cells (MCF-7; MDA-MB-231). Also, the effect of drugs co-delivered in bioresorbable micelles functionalized with biotin (PLA-PEG-BIO; poly(lactide)-co-poly(ethylene glycol)-biotin) was studied. The comparison of effects of the mixture of free drugs and the micelles co-loaded with EpoB and Rap revealed a significant decrease in the cell metabolic activity and survival. Moreover, the dual drug-loaded PLA-PEG-BIO micelles enhanced the cytotoxicity of EpoB and Rap against the tested cells as compared with the free drugs. The blank PLA-PEG-BIO micelles did not affect the tested cells. We expect that mixture of EpoB and Rap may be promising in breast cancer treatment and PLA-PEG-BIO micelles as carrier of these two drugs can be applicable for successful targeted delivery.
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Affiliation(s)
- Alicja Zajdel
- Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland, Sosnowiec, Poland
| | - Adam Wilczok
- Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland, Sosnowiec, Poland
| | - Katarzyna Jelonek
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland
| | - Anna Kaps
- Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland, Sosnowiec, Poland
| | - Monika Musiał-Kulik
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland
| | - Janusz Kasperczyk
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland
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Liu C, Xing W, Yu H, Zhang W, Si T. ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells. Cancer Cell Int 2021; 21:108. [PMID: 33593355 PMCID: PMC7885361 DOI: 10.1186/s12935-021-01800-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 02/03/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Overexpression of ABC transporters is a big challenge on cancer therapy which will lead cancer cells resistance to a series of anticancer drugs. Gedatolisib is a dual PI3K and mTOR inhibitor which is under clinical evaluation for multiple types of malignancies, including colorectal cancer. The growth inhibitory effects of gedatolisib on colorectal cancer cells have been specifically studied. However, the role of ABC transporters on gedatolisib resistance remained unclear. In present study, we illustrated the role of ABC transporters on gedatolisib resistance in colorectal cancer cells. METHODS Cell viability investigations of gedatolisib on colorectal cancer cells were determined by MTT assays. The verapamil and Ko143 reversal studies were determined by MTT assays as well. ABCB1 and/or ABCG2 siRNA interference assays were conducted to verify the role of ABCB1- and ABCG2-overexpression on gedatolisib resistance. The accumulation assays of gedatolisib were conducted using tritium-labeled paclitaxel and mitoxantrone. The effects of gedatolisib on ATPase activity of ABCB1 or ABCG2 were conducted using PREDEASY ATPase Kits. The expression level of ABCB1 and ABCG2 after gedatolisib treatment were conducted by Western blotting and immunofluorescence assays. The well-docked position of gedatolisib with crystal structure of ABCB1 and ABCG2 were simulated by Autodock vina software. One-way ANOVA was used for the statistics analysis. RESULTS Gedatolisib competitively increased the accumulation of tritium-labeled substrate-drugs in both ABCB1- and ABCG2-overexpression colorectal cancer cells. Moreover, gedatolisib significantly increased the protein expression level of ABCB1 and ABCG2 in colorectal cancer cells. In addition, gedatolisib remarkably simulated the ATPase activity of both ABCB1 and ABCG2, suggesting that gedatolisib is a substrate drug of both ABCB1 and ABCG2 transporters. Furthermore, a gedatolisib-resistance colorectal cancer cell line, SW620/GEDA, was selected by increasingly treatment with gedatolisib to SW620 cells. The SW620/GEDA cell line was proved to resistant to gedatolisib and a series of chemotherapeutic drugs, except cisplatin. The ABCB1 and ABCG2 were observed overexpression in SW620/GEDA cell line. CONCLUSIONS These findings suggest that overexpression of ABCB1 and ABCG2 may restrict the efficacy of gedatolisib in colorectal cancer cells, while co-administration with ABC transporter inhibitors may improve the potency of gedatolisib.
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Affiliation(s)
- Changfu Liu
- Department of Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Wenge Xing
- Department of Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Haipeng Yu
- Department of Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Weihao Zhang
- Department of Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Tongguo Si
- Department of Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Mosca L, Ilari A, Fazi F, Assaraf YG, Colotti G. Taxanes in cancer treatment: Activity, chemoresistance and its overcoming. Drug Resist Updat 2021; 54:100742. [PMID: 33429249 DOI: 10.1016/j.drup.2020.100742] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Since 1984, when paclitaxel was approved by the FDA for the treatment of advanced ovarian carcinoma, taxanes have been widely used as microtubule-targeting antitumor agents. However, their historic classification as antimitotics does not describe all their functions. Indeed, taxanes act in a complex manner, altering multiple cellular oncogenic processes including mitosis, angiogenesis, apoptosis, inflammatory response, and ROS production. On the one hand, identification of the diverse effects of taxanes on oncogenic signaling pathways provides opportunities to apply these cytotoxic drugs in a more rational manner. On the other hand, this may facilitate the development of novel treatment modalities to surmount anticancer drug resistance. In the latter respect, chemoresistance remains a major impediment which limits the efficacy of antitumor chemotherapy. Taxanes have shown impact on key molecular mechanisms including disruption of mitotic spindle, mitosis slippage and inhibition of angiogenesis. Furthermore, there is an emerging contribution of cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation to the acquisition of taxane resistance. Hence, these two lines of findings are currently promoting a more rational and efficacious taxane application as well as development of novel molecular strategies to enhance the efficacy of taxane-based cancer treatment while overcoming drug resistance. This review provides a general and comprehensive picture on the use of taxanes in cancer treatment. In particular, we describe the history of application of taxanes in anticancer therapeutics, the synthesis of the different drugs belonging to this class of cytotoxic compounds, their features and the differences between them. We further dissect the molecular mechanisms of action of taxanes and the molecular basis underlying the onset of taxane resistance. We further delineate the possible modalities to overcome chemoresistance to taxanes, such as increasing drug solubility, delivery and pharmacokinetics, overcoming microtubule alterations or mitotic slippage, inhibiting drug efflux pumps or drug metabolism, targeting redox metabolism, immune response, and other cellular functions.
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Affiliation(s)
- Luciana Mosca
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
| | - Francesco Fazi
- Dept. Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University, Via A. Scarpa 14-16, 00161 Rome, Italy
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
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Ghafouri-Fard S, Shoorei H, Abak A, Abbas Raza SH, Pichler M, Taheri M. Role of non-coding RNAs in modulating the response of cancer cells to paclitaxel treatment. Biomed Pharmacother 2020; 134:111172. [PMID: 33360156 DOI: 10.1016/j.biopha.2020.111172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/12/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023] Open
Abstract
Paclitaxel is a chemotherapeutic substance that is administered for treatment of an extensive spectrum of human malignancies. In spite of its potent short-term effects against tumor cells, resistance to paclitaxel occurs in a number of patients precluding its long-term application in these patients. Non-coding RNAs have been shown to influence response of cancer cells to this chemotherapeutic agent via different mechanisms. Mechanistically, these transcripts regulate expression of several genes particularly those being involved in the apoptotic processes. Lots of in vivo and in vitro assays have demonstrated the efficacy of oligonucleotide-mediated microRNAs (miRNA)/ long non-coding RNAs (lncRNA) silencing in enhancement of response of cancer cells to paclitaxel. Therefore, targeted therapies against non-coding RNAs have been suggested as applicable modalities for combatting resistance to this agent. In the present review, we provide a summary of studies which assessed the role of miRNAs and lncRNAs in conferring resistance to paclitaxel.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- 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
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, China
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing in Cancer, Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria; Department of Experimental Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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A Compressive Review about Taxol ®: History and Future Challenges. Molecules 2020; 25:molecules25245986. [PMID: 33348838 PMCID: PMC7767101 DOI: 10.3390/molecules25245986] [Citation(s) in RCA: 192] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/17/2022] Open
Abstract
Taxol®, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol® has been used to treat over one million patients, making it one of the most widely employed antitumoral drugs. Taxol® was the first microtubule targeting agent described in the literature, with its main mechanism of action consisting of the disruption of microtubule dynamics, thus inducing mitotic arrest and cell death. However, secondary mechanisms for achieving apoptosis have also been demonstrated. Despite its wide use, Taxol® has certain disadvantages. The main challenges facing Taxol® are the need to find an environmentally sustainable production method based on the use of microorganisms, increase its bioavailability without exerting adverse effects on the health of patients and minimize the resistance presented by a high percentage of cells treated with paclitaxel. This review details, in a succinct manner, the main aspects of this important drug, from its discovery to the present day. We highlight the main challenges that must be faced in the coming years, in order to increase the effectiveness of Taxol® as an anticancer agent.
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Ghorbani M, Pourjafar F, Saffari M, Asgari Y. Paclitaxel resistance resulted in a stem-like state in triple-negative breast cancer: A systems biology approach. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100800] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Gao M, Liu T, Li J, Guan Q, Wang H, Yan S, Li Z, Zuo D, Zhang W, Wu Y. YAN, a novel microtubule inhibitor, inhibits P-gp and MRP1 function and induces mitotic slippage followed by apoptosis in multidrug-resistant A549/Taxol cells. Toxicol In Vitro 2020; 69:104971. [DOI: 10.1016/j.tiv.2020.104971] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/09/2020] [Accepted: 08/13/2020] [Indexed: 01/05/2023]
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Seidel ZP, Zhang X, MacMullan MA, Graham NA, Wang P, Lee CT. Photo-Triggered Delivery of siRNA and Paclitaxel into Breast Cancer Cells Using Catanionic Vesicles. ACS APPLIED BIO MATERIALS 2020; 3:7388-7398. [DOI: 10.1021/acsabm.0c00503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Zumra Peksaglam Seidel
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
| | - Xiaoyang Zhang
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
| | - Melanie A. MacMullan
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
| | - Nicholas Alexander Graham
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
| | - Pin Wang
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
| | - C. Ted Lee
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
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Wang Z, Dong J, Zhao Q, Ying Y, Zhang L, Zou J, Zhao S, Wang J, Zhao Y, Jiang S. Gold nanoparticle‑mediated delivery of paclitaxel and nucleic acids for cancer therapy (Review). Mol Med Rep 2020; 22:4475-4484. [PMID: 33173972 PMCID: PMC7646735 DOI: 10.3892/mmr.2020.11580] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 09/18/2020] [Indexed: 12/16/2022] Open
Abstract
Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers because they can be engineered to prevent drug insolubility, carry nucleic acid payloads for gene therapy, target specific tumor cell lines, modulate drug release and amplify photothermal therapy. Consequently, the conjugation of paclitaxel with AuNPs to improve antiproliferative and pro‑apoptotic potency may enable improved clinical outcomes. There are currently a number of different AuNPs under development, including simple drug or nucleic acid carriers and targeted AuNPs that are designed to deliver therapeutic payloads to specific cells. The current study reviewed previous research on AuNPs and the development of AuNP‑based paclitaxel delivery.
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Affiliation(s)
- Zhiguang Wang
- Frontier Institute of Science and Technology, State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, P.R. China
| | - Jianyu Dong
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiaojiajie Zhao
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University Medical College, Nanchang, Jiangxi 330006, P.R. China
| | - Lijie Zhang
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
| | - Junrong Zou
- Institute of Urology, The First Affiliated Hospital of Gan'nan Medical University, Ganzhou, Jiangxi 341001, P.R. China
| | - Shuqi Zhao
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
| | - Jiuju Wang
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
| | - Yuan Zhao
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
| | - Shanshan Jiang
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, P.R. China
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