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Wang K, Baird L, Yamamoto M. The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs. Free Radic Biol Med 2025; 233:102-117. [PMID: 40127850 DOI: 10.1016/j.freeradbiomed.2025.03.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/14/2025] [Accepted: 03/22/2025] [Indexed: 03/26/2025]
Abstract
Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2's cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.
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Affiliation(s)
- Ke Wang
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Liam Baird
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Miyagi, Japan.
| | - Masayuki Yamamoto
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Miyagi, Japan.
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Prota G, Berloffa G, Awad W, Vacchini A, Chancellor A, Schaefer V, Constantin D, Littler DR, Colombo R, Nosi V, Mori L, Rossjohn J, De Libero G. Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells. Proc Natl Acad Sci U S A 2025; 122:e2418525122. [PMID: 40354545 DOI: 10.1073/pnas.2418525122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 03/11/2025] [Indexed: 05/14/2025] Open
Abstract
Mitochondria coordinate several metabolic pathways, producing metabolites that influence the immune response in various ways. It remains unclear whether mitochondria impact antigen presentation by the MHC-class-I-related antigen-presenting molecule, MR1, which presents small molecules to MR1-restricted T-lymphocytes. Here, we demonstrate that mitochondrial complex III and the enzyme dihydroorotate dehydrogenase are essential for the cell-surface expression of MR1 and for generating uridine- and thymidine-related compounds that bind to MR1 and are produced upon oxidation by reactive oxygen species. One mitochondria-derived immunogenic formylated metabolite we identified is 5-formyl-deoxyuridine (5-FdU). Structural studies indicate that 5-FdU binds in the A'-antigen-binding pocket of MR1, positioning the deoxyribose toward the surface of MR1 for TCR interaction. 5-FdU stimulates specific T cells and detects circulating T cells when loaded onto MR1-tetramers. 5-FdU-reactive cells resemble adaptive T cells and express the phenotypes of naïve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.
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Affiliation(s)
- Gennaro Prota
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Giuliano Berloffa
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Wael Awad
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Alessandro Vacchini
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Andrew Chancellor
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Verena Schaefer
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Daniel Constantin
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Dene R Littler
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Rodrigo Colombo
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Vladimir Nosi
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Lucia Mori
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4YS, United Kingdom
| | - Gennaro De Libero
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland
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Kweon J, Lim W, Lee H, Kim J, Song G, Jeong W, Ham J. Cypermethrin triggers oxidative stress, apoptosis, and inflammation in bovine mammary glands by disruption of mitogen-activated protein kinase (MAPK) pathways and calcium homeostasis. Reprod Toxicol 2025; 132:108842. [PMID: 39884399 DOI: 10.1016/j.reprotox.2025.108842] [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: 09/18/2024] [Revised: 12/15/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
Cyano-(3-phenoxyphenyl)methyl]3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate (cypermethrin) is a pyrethroid insecticide that is widely used to repel insects, such as cockroaches and ants. In addition to the target insects, its hazards have been outlined for carp; mice; and the nervous, reproductive, and gastrointestinal systems of humans. However, the effects of cypermethrin on the mammary tissue and milk production in dairy cattle remain unknown. Therefore, in the present study, we aimed to elucidate the impact of cypermethrin on dairy cattle using bovine mammary epithelial cells (MAC-T), which play key roles in milk yield and quality maintenance. First, we assessed the effects of cypermethrin on cell viability, proliferation, and cell cycle progression, followed by correlated gene expression analysis. Cypermethrin-treated cells exhibited G1 phase arrest and an increase in the sub G1 population. The population of MAC-T cells in both early and late apoptotic phases was increased following cypermethrin exposure. Moreover, cypermethrin caused mitochondrial calcium overload and diminished the mitochondrial membrane potential in MAC-T cells. We also observed the disruption of mitogen-activated protein kinase (MAPK) cascades and eventually, apoptotic cell death and excessive oxidative stress in cypermethrin-exposed MAC-T cells. In addition, cypermethrin affects the transcription levels related to apoptosis and inflammation, which may lead to the development of clinical morbidities, such as mastitis.
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Affiliation(s)
- Junhun Kweon
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Whasun Lim
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Hojun Lee
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Jinyoung Kim
- Department of Animal Biotechnology, Dankook University, Cheonan 31116, Republic of Korea
| | - Gwonhwa Song
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
| | - Wooyoung Jeong
- Department of Biomedical Sciences, Catholic Kwandong University, Gangneung 25601, Republic of Korea.
| | - Jiyeon Ham
- Division of Animal and Dairy Science, Chungnam National University, Daejeon 34134, Republic of Korea.
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Isik S, Ozcesmeci M, Burat AK, Hamuryudan E, Can O, Serhatli M. Anti-angiogenic effects of cationic zinc (II) phthalocyanine derivatives through photodynamic therapy. Sci Rep 2025; 15:2498. [PMID: 39833179 PMCID: PMC11756419 DOI: 10.1038/s41598-024-84674-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 12/25/2024] [Indexed: 01/22/2025] Open
Abstract
In this study, the in vitro photodynamic therapy (PDT) activity of two zinc phthalocyanines (ZnPc1 and ZnPc2) was systematically examined in human umbilical vein endothelial cells, focusing on PDT-induced cytotoxicity, reactive oxygen species (ROS) generation, and inhibition of angiogenic processes. Both the ZnPcs demonstrated minimal cytotoxicity in the absence of light, confirming their safety as photosensitizers. ZnPc-PDT led to significant cell death via apoptosis. ZnPc1 exhibited enhanced ROS generation, particularly at elevated concentrations. Furthermore, ZnPc1-mediated PDT showed more pronounced inhibition of endothelial cell migration, invasion, and capillary-like tube formation than ZnPc2. Wound-healing assays revealed a substantial delay in human umbilical vein endothelial cell (HUVEC) migration following ZnPc1-PDT, which also displayed a more significant inhibition of VEGF-induced directional migration and invasion. Endothelial tube formation was more effectively disrupted by ZnPc1-PDT, even at lower concentrations, compared to ZnPc2. Collectively, these findings highlight the superior cytotoxic and anti-angiogenic properties of ZnPc1 compared with ZnPc2, highlighting its potential as a highly effective photosensitizer for photodynamic therapy. The ability of ZnPc1 to simultaneously target tumor cells and disrupt angiogenesis establishes it as a potent candidate for integrated cancer therapies that combine both antitumor and antiangiogenic strategies, offering a more effective approach to combat cancer progression.
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Affiliation(s)
- Seyma Isik
- TUBITAK Marmara Research Center, Climate Change and Life Sciences, Biotechnology Research Group, 41470, Kocaeli, Turkey
- Department of Medical Biotechnology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752, Istanbul, Turkey
| | - Mukaddes Ozcesmeci
- Department of Chemistry, Istanbul Technical University, 34469, Istanbul, Turkey
| | - Ayfer Kalkan Burat
- Department of Chemistry, Istanbul Technical University, 34469, Istanbul, Turkey
| | - Esin Hamuryudan
- Department of Chemistry, Istanbul Technical University, 34469, Istanbul, Turkey
| | - Ozge Can
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752, Istanbul, Turkey.
| | - Muge Serhatli
- TUBITAK Marmara Research Center, Climate Change and Life Sciences, Biotechnology Research Group, 41470, Kocaeli, Turkey.
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Prasad K, Saggam A, Guruprasad KP, Tillu G, Patwardhan B, Satyamoorthy K. Molecular mechanisms of Asparagus racemosus willd. and Withania somnifera (L.) Dunal as chemotherapeutic adjuvants for breast cancer treatment. JOURNAL OF ETHNOPHARMACOLOGY 2024; 331:118261. [PMID: 38685363 DOI: 10.1016/j.jep.2024.118261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/02/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Despite various treatment modalities, the progression and metastasis of breast cancer (BC) are grave concerns due to the alarming disease-free survival rate (DFS) and overall survival rate (OS) of affected patients. Over the years, many antibiotics, synthetic compounds, medicinal plant isolates and polyherbal combinations have been used as adjuvants in therapy for the management of primary and secondary tumors. Paclitaxel (PTX)-based chemotherapy for breast cancer causes multiple adverse side effects in patients. Withania somnifera (L.) Dunal (WS) and Asparagus racemosus Willd. (AR) as Ayurveda-inspired plant-based adjuvants were investigated for their anticancer effects on MDA-MB-231 and 4T1 cells in mouse model systems. AIM OF THE STUDY This study focused on evaluating the adjuvant properties of WS and AR plant extracts with PTX and their effectiveness over PTX alone in terms of tumor inhibition. MATERIALS AND METHODS The effects of WS and AR on DNA double-strand breaks (DSBs), senescence induction and mitochondrial functions were evaluated in BC cells in vitro. The potential for cancer stem cell (CSC) inhibition was evaluated via mammosphere formation assays and CD44/CD24 immunostaining. In vivo tumor growth studies were conducted in athymic BALB/c mice for MDA-MB-231 cells and in BALB/c mice for 4T1 cells. RESULTS Induction of senescence was evident due to DSBs induced by the WS and AR extracts. Mammosphere formation and CD44/CD24 CSC markers were reduced after treatment with WS, AR or the combination of both in MCF-7 cells. WS or AR inhibited epithelial-to-mesenchymal transition (EMT). In vivo studies demonstrated that tumor growth inhibition was more pronounced in the treated group than in the PTX alone group and the untreated control group. CONCLUSION Our study showed that the use of WS or AR plant hydroalcoholic extracts in combination with paclitaxel (PTX) has better effects on sensitivity and efficacy than PTX alone, as demonstrated in in vitro BC cells and mouse models with BC cell grafts. Hence, scheduling adjuvant therapy with WS or AR alone or combined with PTX can be advantageous for the management of triple-negative BC (TNBC). Further studies are warranted in human clinical conditions to ascertain the efficacy of these treatments.
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Affiliation(s)
- Keshava Prasad
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
| | - Akash Saggam
- Ayush Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, 411007, India.
| | - Kanive Parashiva Guruprasad
- Centre for Ayurvedic Biology, Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
| | - Girish Tillu
- Ayush Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, 411007, India.
| | - Bhushan Patwardhan
- Ayush Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, 411007, India.
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India; SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara (SDM) University, Manjushree Nagar, Sattur, Dharwad, Karnataka, 580009, India.
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6
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Ali T, Li D, Ponnamperumage TNF, Peterson AK, Pandey J, Fatima K, Brzezinski J, Jakusz JAR, Gao H, Koelsch GE, Murugan DS, Peng X. Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment. Cancers (Basel) 2024; 16:2171. [PMID: 38927877 PMCID: PMC11201821 DOI: 10.3390/cancers16122171] [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: 05/02/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer cells show altered antioxidant defense systems, dysregulated redox signaling, and increased generation of reactive oxygen species (ROS). Targeting cancer cells through ROS-mediated mechanisms has emerged as a significant therapeutic strategy due to its implications in cancer progression, survival, and resistance. Extensive research has focused on selective generation of H2O2 in cancer cells for selective cancer cell killing by employing various strategies such as metal-based prodrugs, photodynamic therapy, enzyme-based systems, nano-particle mediated approaches, chemical modulators, and combination therapies. Many of these H2O2-amplifying approaches have demonstrated promising anticancer effects and selectivity in preclinical investigations. They selectively induce cytotoxicity in cancer cells while sparing normal cells, sensitize resistant cells, and modulate the tumor microenvironment. However, challenges remain in achieving selectivity, addressing tumor heterogeneity, ensuring efficient delivery, and managing safety and toxicity. To address those issues, H2O2-generating agents have been combined with other treatments leading to optimized combination therapies. This review focuses on various chemical agents/approaches that kill cancer cells via H2O2-mediated mechanisms. Different categories of compounds that selectively generate H2O2 in cancer cells are summarized, their underlying mechanisms and function are elucidated, preclinical and clinical studies as well as recent advancements are discussed, and their prospects as targeted therapeutic agents and their therapeutic utility in combination with other treatments are explored. By understanding the potential of these compounds, researchers can pave the way for the development of effective and personalized cancer treatments.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Xiaohua Peng
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211, USA; (T.A.); (D.L.); (T.N.F.P.); (A.K.P.); (J.P.); (K.F.); (J.B.); (J.A.R.J.); (H.G.); (G.E.K.); (D.S.M.)
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7
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Vacchini A, Chancellor A, Yang Q, Colombo R, Spagnuolo J, Berloffa G, Joss D, Øyås O, Lecchi C, De Simone G, Beshirova A, Nosi V, Loureiro JP, Morabito A, De Gregorio C, Pfeffer M, Schaefer V, Prota G, Zippelius A, Stelling J, Häussinger D, Brunelli L, Villalta P, Lepore M, Davoli E, Balbo S, Mori L, De Libero G. Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells. Sci Immunol 2024; 9:eadn0126. [PMID: 38728413 DOI: 10.1126/sciimmunol.adn0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024]
Abstract
MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I-related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.
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Affiliation(s)
- Alessandro Vacchini
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Andrew Chancellor
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Qinmei Yang
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Rodrigo Colombo
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Julian Spagnuolo
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Giuliano Berloffa
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Daniel Joss
- Department of Chemistry, University of Basel, Basel 4056, Switzerland
| | - Ove Øyås
- Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, Basel 4058, Switzerland
| | - Chiara Lecchi
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Giulia De Simone
- Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano 20156, Italy
| | - Aisha Beshirova
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Vladimir Nosi
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - José Pedro Loureiro
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Aurelia Morabito
- Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano 20156, Italy
| | - Corinne De Gregorio
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Michael Pfeffer
- Department of Chemistry, University of Basel, Basel 4056, Switzerland
| | - Verena Schaefer
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Gennaro Prota
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Alfred Zippelius
- Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Jörg Stelling
- Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, Basel 4058, Switzerland
| | - Daniel Häussinger
- Department of Chemistry, University of Basel, Basel 4056, Switzerland
| | - Laura Brunelli
- Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano 20156, Italy
| | - Peter Villalta
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
| | - Marco Lepore
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Enrico Davoli
- Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano 20156, Italy
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Lucia Mori
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Gennaro De Libero
- Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland
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Mao QQ, Ji XC, Zhang JN, Teng WF, Zhou SC. A novel approach for transforming breast cancer stem cells into endothelial cells. Exp Ther Med 2024; 27:74. [PMID: 38264426 PMCID: PMC10804376 DOI: 10.3892/etm.2023.12362] [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: 08/19/2023] [Accepted: 11/27/2023] [Indexed: 01/25/2024] Open
Abstract
Tumor vascular endothelial cells play a pivotal in the tumor microenvironment, influencing the proliferation, invasion, and metastasis of tumor progression. The present study investigated a novel method for inducing the transformation of breast cancer stem cells into endothelial cells, providing a cellular model investigating anti-angiogenic mechanisms in vitro. The breast cancer cell line MCF-7 was used, and the expression of CD133 was initially detected using flow cytometry. CD133+ breast cancer cells were purified using immunomagnetic bead sorting technology, yielding an MCF-7CD133+ subpopulation. The proliferation ability of these cells was assessed using an MTT assay, while their microsphere formation ability was evaluated using a microsphere formation assay. Post-transformation in an optimized endothelial cell culture medium, expression of endothelial cell markers CD31 and CD105 were detected using flow cytometry. Endothelial cell tube formation assays and DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL) assays were employed to analyze the endothelial cell function of the MCF-7CD133+ cells. MDM2/CEN12 gene amplification was detected through fluorescence in situ hybridization (FISH). The MCF-7 breast cancer cell line exhibited 1.7±0.3% trace cells expressing the stem cell surface marker CD133. After anti-CD133 immunomagnetic bead sorting, MCF-7CD133+ and MCF-7CD133- subpopulation cells were obtained, with CD133 expression rates of 85.6±2.8 and 0.18±0.08%, respectively. MTT assay results demonstrated that, after 7 days, the proliferation rate of MCF-7CD133+ cells was significantly higher compared with MCF-7CD133- cells. MCF-7CD133+ subpopulation cells displayed strong stem cell characteristics, growing in suspension in serum-free media and forming tumor cell spheres. In contrast, MCF-7CD133- cells failed to form microspheres. After culturing cells in endothelial cell differentiation and maintenance media, the percentage of MCF-7CD133+ cells before and after endothelial cell culture was 0.3±0.16 and 81.4±8.37% for CD31+ cells and 0.2±0.08 and 83.8±7.24% for CD105+ cells, respectively. Vascular-like structure formation and Ac-LDL phagocytosis with red fluorescence in the tube formation assays confirmed endothelial cell function in the MCF-7CD133+ cells. FISH was used to verify MDM2/CEN12 gene amplification in the induced MCF-7CD133+ cells, indicating tumor cell characteristics. The modified endothelial cell transformation medium effectively induced differentiated tumor stem cells to express vascular endothelial cell markers and exhibit endothelial functions, ideal for in vitro anti-angiogenesis research.
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Affiliation(s)
- Qi-Qi Mao
- Department of Thyroid and Breast Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, Zheijiang 315040, P.R. China
| | - Xiao-Chun Ji
- Department of Thyroid and Breast Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, Zheijiang 315040, P.R. China
| | - Jia-Nan Zhang
- Department of Thyroid and Breast Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, Zheijiang 315040, P.R. China
| | - Wei-Feng Teng
- Department of Thyroid and Breast Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, Zheijiang 315040, P.R. China
| | - Shao-Cheng Zhou
- Department of Thyroid and Breast Surgery, Ningbo Medical Center, Lihuili Hospital, Ningbo, Zheijiang 315040, P.R. China
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9
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Ahmed M, Semreen AM, Giddey AD, Ramadan WS, El-Awady R, Soares NC, El-Huneidi W, Bustanji Y, Alqudah MAY, Alzoubi KH, Semreen MH. Proteomic and metabolomic signatures of U87 glioblastoma cells treated with cisplatin and/or paclitaxel. Ann Med 2024; 55:2305308. [PMID: 38253025 PMCID: PMC10810643 DOI: 10.1080/07853890.2024.2305308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/19/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Glioblastoma (GBM) is a primary malignancy of the central nervous system and is classified as a grade IV astrocytoma by the World Health Organization (WHO). Although GBM rarely metastasizes, its prognosis remains poor. Moreover, the standard treatment for GBM, temozolomide (TMZ), is associated with chemoresistance, which is a major factor behind GBM-related deaths. Investigating drugs with repurposing potential in the context of GBM is worthwhile to bypass lengthy bench-to-bedside research. The field of omics has garnered significant interest in scientific research because of its potential to delineate the intricate regulatory network underlying tumor development. In particular, proteomic and metabolomic analyses are powerful approaches for the investigation of metabolic enzymes and intermediate metabolites since they represent the functional end of the cancer phenotype. METHODS We chose two of the most widely prescribed anticancer drugs, cisplatin and paclitaxel. To our knowledge, the current literature lacks studies examining their effects on metabolic and proteomic alterations in GBM. We employed the mass spectrometry technological platform 'UHPLC-Q-TOF-MS/MS' to examine the changes in the proteome and metabolome profiles of the U87 cell line with defined concentrations of cisplatin and/or paclitaxel via an untargeted approach. RESULTS A total of 1,419 distinct proteins and 90 metabolites were generated, and subsequent analysis was performed. We observed that upon treatment with cisplatin (9.5 μM), U87 cells exhibited apparent efforts to cope with this exogenous stressor, understanding the effect of paclitaxel (5.3 μM) on altering the transport machinery of the cell, and how the combination of cisplatin and/or paclitaxel suggests potential interactions with promising benefits in GBM therapeutics. CONCLUSION Our research provides a detailed map of alterations in response to cisplatin and paclitaxel treatment, provides crucial insights into the molecular basis of their action, and paves the way for further research to identify molecular targets for this elusive malignancy.
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Affiliation(s)
- Munazza Ahmed
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Ahlam M. Semreen
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Alexander D. Giddey
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Wafaa S. Ramadan
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Raafat El-Awady
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Nelson C. Soares
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Laboratory of Proteomics, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA), Lisbon, Portugal
| | - Waseem El-Huneidi
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Yasser Bustanji
- Department of Basic and Clinical Pharmacology, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- School of Pharmacy, The University of Jordan, Amman, Jordan
| | - Mohammad A. Y. Alqudah
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Karem H. Alzoubi
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohammad H. Semreen
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
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10
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Lim YJ, Kim HS, Bae S, So KA, Kim TJ, Lee JH. Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells. Molecules 2024; 29:274. [PMID: 38202856 PMCID: PMC10780346 DOI: 10.3390/molecules29010274] [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: 10/27/2023] [Revised: 12/19/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024] Open
Abstract
Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.
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Affiliation(s)
- Ye Jin Lim
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea; (Y.J.L.); (H.S.K.); (S.B.)
| | - Hee Su Kim
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea; (Y.J.L.); (H.S.K.); (S.B.)
| | - Seunghee Bae
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea; (Y.J.L.); (H.S.K.); (S.B.)
| | - Kyeong A So
- Department of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea; (K.A.S.); (T.J.K.)
| | - Tae Jin Kim
- Department of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea; (K.A.S.); (T.J.K.)
| | - Jae Ho Lee
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea; (Y.J.L.); (H.S.K.); (S.B.)
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11
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Shen A, Sun Y, Wang G, Meng X, Ren X, Wan Q, Lv Q, Wang X, Ni J, Li M, Ma X, Xu Y, Jiang Y, Wang F, Cheng Y, Wang P. An Adaptable Nanoprobe Integrated with Quantitative T 1 -Mapping MRI for Accurate Differential Diagnosis of Multidrug-Resistant Lung Cancer. Adv Healthc Mater 2023; 12:e2300684. [PMID: 37714524 DOI: 10.1002/adhm.202300684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Indexed: 09/17/2023]
Abstract
Multidrug resistance (MDR) is one of the major factors causing failure of non-small-cell lung cancer (NSCLC) chemotherapy. Real-time and accurate differentiation between drug-resistant and sensitive NSCLC is of primary importance for guiding the subsequent treatments and improving the therapeutic outcome. However, there is no effective method to provide such an accurate differentiation. This study creates an innovative strategy of integrating H2 O2 -responsive nanoprobes with the quantitative T1 -mapping magnetic resonance imaging (MRI) technique to achieve an accurate differential diagnosis between drug-resistant and sensitive NSCLC in light of differences in H2 O2 content in the tumor microenvironment (TME). The result demonstrates that the synthesized MIL-53(Fe)@MnO2 nanocomposites possess an excellent capability of shortening the cancer longitudinal relaxation time (T1 ) when meeting H2 O2 in TME. T1 -mapping MRI could sensitively detect this T1 variation (about 2.6-fold that of T1-weighted imaging (T1 WI)) to accurately differentiate the H2 O2 content between drug-resistant and sensitive NSCLC. In addition, the quantitative data provided by the T1 -mapping MRI dedicates correct comparison across imaging tests and is more reliable than T1 WI, thus giving it a chance for precise assessment of the anti-cancer effect. This innovative strategy of merging TME adaptable nanoprobes with the quantitative MRI technique provides a new approach for the precise diagnosis of multidrug-resistant NSCLC.
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Affiliation(s)
- Aijun Shen
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Yanhong Sun
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200438, China
| | - Gangmin Wang
- Department of Urology, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Xianfu Meng
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Tongji University Cancer Center, Shanghai, 200072, China
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200438, China
| | - Xihui Ren
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Qingxuan Wan
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Qi Lv
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Xiangbin Wang
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Jiong Ni
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Minghua Li
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Xiaolong Ma
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Yun Xu
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Yutao Jiang
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Fang Wang
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - YingSheng Cheng
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Peijun Wang
- Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
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12
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Natarajan D, Prasad NR, Sudharsan M, Bharathiraja P, Lakra DS. Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system. Cell Biochem Funct 2023; 41:1305-1318. [PMID: 37792847 DOI: 10.1002/cbf.3865] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/06/2023] [Accepted: 09/16/2023] [Indexed: 10/06/2023]
Abstract
The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration-approved gold-containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel-sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel-mediated cytotoxicity in a concentration-dependent manner in both MDA-MB-231 and MCF-7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7-diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine-123 staining) in a concentration-dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel-treated breast cancer cells compared to paclitaxel-alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy.
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Affiliation(s)
- Deepika Natarajan
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - N Rajendra Prasad
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - M Sudharsan
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Pradhapsingh Bharathiraja
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Deepa Swati Lakra
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
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13
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Rathnayake K, Patel U, Hunt EC, Singh N. Fabrication of a Dual-Targeted Liposome-Coated Mesoporous Silica Core-Shell Nanoassembly for Targeted Cancer Therapy. ACS OMEGA 2023; 8:34481-34498. [PMID: 37779923 PMCID: PMC10536893 DOI: 10.1021/acsomega.3c02901] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023]
Abstract
Nanoparticles have been suggested as drug-delivery systems for chemotherapeutic drugs to allow for controlled drug release profiles and selectivity to target cancer cells. In addition, nanoparticles can be used for the in situ generation and amplification of reactive oxygen species (ROS), which have been shown to be a promising strategy for cancer treatment. Thus, a targeted nanoscale drug-delivery platform could be used to synergistically improve cancer treatment by the action of chemotherapeutic drugs and ROS generation. Herein, we propose a promising chemotherapy strategy where the drug-loaded nanoparticles generate high doses of ROS together with the loaded ROS-generating chemotherapeutic drugs, which can damage the mitochondria and activate cell death, potentiating the therapeutic outcome in cancer therapy. In the present study, we have developed a dual-targeted drug-delivery nanoassembly consisting of a mesoporous silica core loaded with the chemotherapeutic, ROS-generating drug, paclitaxel (Px), and coated with a liposome layer for controlled drug release. Two different lung cancer-targeting ligands, folic acid and peptide GE11, were used to target the overexpressed nonsmall lung cancer receptors to create the final nanoassembly (MSN@Px) L-GF. Upon endocytosis by the cancer cells, the liposome layer was degraded by the intracellular lipases, and the drug was rapidly released at a rate of 65% within the first 20 h. In vitro studies confirmed that this nanoassembly was 8-fold more effective in cancer therapy compared to the free drug Px.
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Affiliation(s)
- Kavini Rathnayake
- Department of Chemistry, The
University of Alabama in Huntsville, Huntsville, Alabama 35899, United States
| | - Unnati Patel
- Department of Chemistry, The
University of Alabama in Huntsville, Huntsville, Alabama 35899, United States
| | - Emily C. Hunt
- Department of Chemistry, The
University of Alabama in Huntsville, Huntsville, Alabama 35899, United States
| | - Nirupama Singh
- Department of Chemistry, The
University of Alabama in Huntsville, Huntsville, Alabama 35899, United States
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14
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Marini HR, Facchini BA, di Francia R, Freni J, Puzzolo D, Montella L, Facchini G, Ottaiano A, Berretta M, Minutoli L. Glutathione: Lights and Shadows in Cancer Patients. Biomedicines 2023; 11:2226. [PMID: 37626722 PMCID: PMC10452337 DOI: 10.3390/biomedicines11082226] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting.
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Affiliation(s)
- Herbert Ryan Marini
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (H.R.M.); (L.M.)
| | - Bianca Arianna Facchini
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80133 Napoli, Italy;
| | - Raffaele di Francia
- Gruppo Oncologico Ricercatori Italiani (GORI-ONLUS), 33170 Pordenone, Italy;
| | - José Freni
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Domenico Puzzolo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Liliana Montella
- Division of Medical Oncology, “Santa Maria delle Grazie” Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy; (L.M.); (G.F.)
| | - Gaetano Facchini
- Division of Medical Oncology, “Santa Maria delle Grazie” Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy; (L.M.); (G.F.)
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, 80131 Napoli, Italy;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (H.R.M.); (L.M.)
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (H.R.M.); (L.M.)
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15
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Gür FM, Bilgiç S. Silymarin, an antioxidant flavonoid, protects the liver from the toxicity of the anticancer drug paclitaxel. Tissue Cell 2023; 83:102158. [PMID: 37459721 DOI: 10.1016/j.tice.2023.102158] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/28/2023]
Abstract
One of the biggest factors that negatively affect the cancer treatment plan is the toxic effects of chemotherapeutics on non-target cells and tissues. This information prompted us to investigate the protective effects of silymarin (SL), a hepatoprotective agent, against the hepatotoxic effects of the anticancer drug paclitaxel (PAC). Four groups were formed from 28 rats as control, PAC (2 mg/kg), SL (100 mg/kg) and PAC + SL (combination of PAC with SL). After completing the experimental procedures, the tissues collected after anesthesia were analyzed by Western blot, qRT-PCR, biochemical, stereological, immunohistochemical, and histopathological techniques. Administration of PAC significantly increased the expression of tumor necrosis factor-alpha (TNF-α), Bax, cytochrome-c (cyt-c), and active caspase-3, as well as malondialdehyde (MDA) levels in liver tissue and decreased glutathione (GSH) levels compared with the control group. PAC also resulted in a significant increase in serum triglyceride (TG), cholesterol (CH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the control group. Pathological changes such as microvesicular steatosis, the formation of Councilman bodies, an increase in total sinusoidal volume, and a decrease in the total number of hepatocytes were observed in the liver tissue of the PAC group. Almost all analysis results in the PAC + SL group were similar to those in the control group, and no significant pathological alterations were observed in this group. The data obtained show that SL protects the liver from the harmful effects of PAC, especially thanks to its TNF-α suppressor, anti-inflammatory, anti-apoptotic and antioxidant effects. Based on this result, in cases where PAC is used in cancer treatment, it can be recommended to be used together with SL to prevent harmful effects on healthy liver tissue and to continue treatment uninterruptedly and effectively.
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Affiliation(s)
- Fatih Mehmet Gür
- Department of Histology and Embryology, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey.
| | - Sedat Bilgiç
- Department of Medical Biochemistry, Vocational School of Health Services, Adıyaman University, Adıyaman, Turkey.
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16
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Maeda J, Jepson B, Sadahiro K, Murakami M, Sakai H, Heishima K, Akao Y, Kato TA. PARP deficiency causes hypersensitivity to Taxol through oxidative stress induced DNA damage. Mutat Res 2023; 827:111826. [PMID: 37300987 DOI: 10.1016/j.mrfmmm.2023.111826] [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: 03/03/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023]
Abstract
Taxol is an antitumor drug derived from the bark of the Pacific Yew tree that inhibits microtubule disassembly, resulting in cell cycle arrest in late G2 and M phases. Additionally, Taxol increases cellular oxidative stress by generating reactive oxygen species. We hypothesized that the inhibition of specific DNA repair machinery/mechanisms would increase cellular sensitivity to the oxidative stress capacity of Taxol. Initial screening using Chinese hamster ovary (CHO) cell lines demonstrated that base excision repair deficiency, especially PARP deficiency, caused cellular Taxol hypersensitivity. Taxane diterpenes-containing Taxus yunnanensis extract also showed hypertoxicity in PARP deficient cells, which was consistent with other microtubule inhibitors like colcemid, vinblastine, and vincristine. Acute exposure of 50 nM Taxol treatment induced both significant cytotoxicity and M-phase arrest in PARP deficient cells, but caused neither significant cytotoxicity nor late G2-M cell cycle arrest in wild type cells. Acute exposure of 50 nM Taxol treatment induced oxidative stress and DNA damage. The antioxidant Ascorbic acid 2 glucoside partially reduced the cytotoxicity of Taxol in PARP deficient cell lines. Finally, the PARP inhibitor Olaparib increased cytotoxicity of Taxol in wild type CHO cells and two human cancer cell lines. Our study clearly demonstrates that cytotoxicity of Taxol would be enhanced by inhibiting PARP function as an enzyme implicated in DNA repair for oxidative stress.
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Affiliation(s)
- Junko Maeda
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Ben Jepson
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Kohei Sadahiro
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Mami Murakami
- Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Hiroki Sakai
- Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kazuki Heishima
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Yukihiro Akao
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Takamitsu A Kato
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.
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17
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Stemberger MB, Ju JA, Thompson KN, Mathias TJ, Jerrett AE, Chang KT, Ory EC, Annis DA, Mull ML, Gilchrist DE, Vitolo MI, Martin SS. Hydrogen Peroxide Induces α-Tubulin Detyrosination and Acetylation and Impacts Breast Cancer Metastatic Phenotypes. Cells 2023; 12:1266. [PMID: 37174666 PMCID: PMC10177274 DOI: 10.3390/cells12091266] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/23/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Levels of hydrogen peroxide are highly elevated in the breast tumor microenvironment compared to normal tissue. Production of hydrogen peroxide is implicated in the mechanism of action of many anticancer therapies. Several lines of evidence suggest hydrogen peroxide mediates breast carcinogenesis and metastasis, though the molecular mechanism remains poorly understood. This study elucidates the effects of exposure to elevated hydrogen peroxide on non-tumorigenic MCF10A mammary epithelial cells, tumorigenic MCF7 cells, and metastatic MDA-MB-231 breast cancer cells. Hydrogen peroxide treatment resulted in a dose- and time-dependent induction of two α-tubulin post-translational modifications-de-tyrosination and acetylation-both of which are markers of poor patient prognosis in breast cancer. Hydrogen peroxide induced the formation of tubulin-based microtentacles in MCF10A and MDA-MB-231 cells, which were enriched in detyrosinated and acetylated α-tubulin. However, the hydrogen peroxide-induced microtentacles did not functionally promote metastatic phenotypes of cellular reattachment and homotypic cell clustering. These data establish for the first time that microtentacle formation can be separated from the functions to promote reattachment and clustering, which indicates that there are functional steps that remain to be identified. Moreover, signals in the primary tumor microenvironment may modulate α-tubulin post-translational modifications and induce microtentacles; however, the functional consequences appear to be context-dependent.
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Affiliation(s)
- Megan B. Stemberger
- Graduate Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201, USA
| | - Julia A. Ju
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
| | - Keyata N. Thompson
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA
| | - Trevor J. Mathias
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
| | - Alexandra E. Jerrett
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA
| | - Katarina T. Chang
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
| | - Eleanor C. Ory
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA
| | - David A. Annis
- Graduate Program in Epidemiology and Human Genetics, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, USA
| | - Makenzy L. Mull
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
| | - Darin E. Gilchrist
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
| | - Michele I. Vitolo
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA
- Departments of Pharmacology and Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, USA
| | - Stuart S. Martin
- Graduate Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201, USA
- Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA
- Graduate Program in Epidemiology and Human Genetics, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, USA
- Departments of Pharmacology and Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, USA
- United States Department of Veterans Affairs, VA Maryland Health Care System, 10 18 N. Greene St., Baltimore, MD 21201, USA
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18
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Song J, Cheng M, Xie Y, Li K, Zang X. Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug. J Nanobiotechnology 2023; 21:93. [PMID: 36927803 PMCID: PMC10018933 DOI: 10.1186/s12951-023-01842-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Immunotherapy has emerged as a promising therapeutic strategy for cancer therapy. However, the therapeutic efficacy has been distracted due to poor immunogenicity and immunosuppressive tumor microenvironment. In this study, a self-augmented reactive oxygen species (ROS) responsive nanocarrier with immunogenic inducer paclitaxel (PTX) and indoleamine 2,3-dixoygenase 1 (IDO1) blocker 1-methyl-D, L-tryptophan (1-MT) co-entrapment was developed for tumor rejection. The carrier was composed of poly (ethylene glycol) (PEG) as hydrophilic segments, enzyme cleavable 1-MT ester and ROS-sensitive peroxalate conjugation as hydrophobic blocks. The copolymer could self-assemble into prodrug-based nanoparticles with PTX, realizing a positive feedback loop of ROS-accelerated PTX release and PTX induced ROS generation. Our nanoparticles presented efficient immunogenic cell death (ICD) which provoked antitumor immune responses with high effector T cells infiltration. Meanwhile immunosuppressive tumor microenvironment was simultaneously modulated with reduced regulatory T cells (Tregs) and M2-tumor associated macrophages (M2-TAMs) infiltration mediated by IDO inhibition. The combination of PTX and 1-MT achieved significant primary tumor regression and reduction of lung metastasis in 4T1 tumor bearing mice. Therefore, the above results demonstrated co-delivery of immunogenic inducer and IDO inhibitor using the ROS amplifying nanoplatform with potent potential for tumor chemoimmunotherapy.
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Affiliation(s)
- Jinxiao Song
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, People's Republic of China
| | - Mingyang Cheng
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, People's Republic of China
| | - Yi Xie
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, People's Republic of China
| | - Kangkang Li
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, People's Republic of China
| | - Xinlong Zang
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, People's Republic of China.
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19
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Morgan RN, Saleh SE, Farrag HA, Aboshanab KM. Gamma radiation coupled ADP-ribosyl transferase activity of Pseudomonas aeruginosa PE24 moiety. Appl Microbiol Biotechnol 2023; 107:1765-1784. [PMID: 36808279 PMCID: PMC10006270 DOI: 10.1007/s00253-023-12401-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 02/21/2023]
Abstract
The ADP-ribosyl transferase activity of P. aeruginosa PE24 moiety expressed by E. coli BL21 (DE3) was assessed on nitrobenzylidene aminoguanidine (NBAG) and in vitro cultured cancer cell lines. Gene encoding PE24 was isolated from P. aeruginosa isolates, cloned into pET22b( +) plasmid, and expressed in E. coli BL21 (DE3) under IPTG induction. Genetic recombination was confirmed by colony PCR, the appearance of insert post digestion of engineered construct, and protein electrophoresis using sodium dodecyl-sulfate polyacrylamide gel (SDS-PAGE). The chemical compound NBAG has been used to confirm PE24 extract ADP-ribosyl transferase action through UV spectroscopy, FTIR, c13-NMR, and HPLC before and after low-dose gamma irradiation (5, 10, 15, 24 Gy). The cytotoxicity of PE24 extract alone and in combination with paclitaxel and low-dose gamma radiation (both 5 Gy and one shot 24 Gy) was assessed on adherent cell lines HEPG2, MCF-7, A375, OEC, and Kasumi-1 cell suspension. Expressed PE24 moiety ADP-ribosylated NBAG as revealed by structural changes depicted by FTIR and NMR, and the surge of new peaks at different retention times from NBAG in HPLC chromatograms. Irradiating recombinant PE24 moiety was associated with a reduction in ADP-ribosylating activity. The PE24 extract IC50 values were < 10 μg/ml with an acceptable R2 value on cancer cell lines and acceptable cell viability at 10 μg/ml on normal OEC. Overall, the synergistic effects were observed upon combining PE24 extract with low-dose paclitaxel demonstrated by the reduction in IC50 whereas antagonistic effects and a rise in IC50 values were recorded after irradiation by low-dose gamma rays. KEY POINTS: • Recombinant PE24 moiety was successfully expressed and biochemically analyzed. • Low-dose gamma radiation and metal ions decreased the recombinant PE24 cytotoxic activity. • Synergism was observed upon combining recombinant PE24 with low-dose paclitaxel.
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Affiliation(s)
- Radwa N. Morgan
- National Centre for Radiation Research and Technology (NCRRT), Drug Radiation Research Department, Egyptian Atomic Energy Authority (EAEA), Ahmed El-Zomor Street, Nasr City, 11787 Cairo Egypt
| | - Sarra E. Saleh
- Microbiology and Immunology Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, 11566 Cairo Egypt
| | - Hala A. Farrag
- National Centre for Radiation Research and Technology (NCRRT), Drug Radiation Research Department, Egyptian Atomic Energy Authority (EAEA), Ahmed El-Zomor Street, Nasr City, 11787 Cairo Egypt
| | - Khaled M. Aboshanab
- Microbiology and Immunology Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, 11566 Cairo Egypt
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20
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Mohammadpour-Haratbar A, Boraei SBA, Zare Y, Rhee KY, Park SJ. Graphene-Based Electrochemical Biosensors for Breast Cancer Detection. BIOSENSORS 2023; 13:bios13010080. [PMID: 36671915 PMCID: PMC9855997 DOI: 10.3390/bios13010080] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 06/04/2023]
Abstract
Breast cancer (BC) is the most common cancer in women, which is also the second most public cancer worldwide. When detected early, BC can be treated more easily and prevented from spreading beyond the breast. In recent years, various BC biosensor strategies have been studied, including optical, electrical, electrochemical, and mechanical biosensors. In particular, the high sensitivity and short detection time of electrochemical biosensors make them suitable for the recognition of BC biomarkers. Moreover, the sensitivity of the electrochemical biosensor can be increased by incorporating nanomaterials. In this respect, the outstanding mechanical and electrical performances of graphene have led to an increasingly intense study of graphene-based materials for BC electrochemical biosensors. Hence, the present review examines the latest advances in graphene-based electrochemical biosensors for BC biosensing. For each biosensor, the detection limit (LOD), linear range (LR), and diagnosis technique are analyzed. This is followed by a discussion of the prospects and current challenges, along with potential strategies for enhancing the performance of electrochemical biosensors.
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Affiliation(s)
- Ali Mohammadpour-Haratbar
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1715424313, Iran
| | - Seyyed Behnam Abdollahi Boraei
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1715424313, Iran
| | - Yasser Zare
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1715424313, Iran
| | - Kyong Yop Rhee
- Department of Mechanical Engineering (BK21 Four), College of Engineering, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Soo-Jin Park
- Department of Chemistry, Inha University, Incheon 22212, Republic of Korea
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21
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Balaji S, Neupane R, Malla S, Khupse R, Amawi H, Kumari S, Tukaramrao DB, Chattopadhyay S, Ashby CR, Boddu SHS, Karthikeyan C, Trivedi P, Raman D, Tiwari AK. IND-2, a Quinoline Derivative, Inhibits the Proliferation of Prostate Cancer Cells by Inducing Oxidative Stress, Apoptosis and Inhibiting Topoisomerase II. LIFE (BASEL, SWITZERLAND) 2022; 12:life12111879. [PMID: 36431014 PMCID: PMC9693996 DOI: 10.3390/life12111879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022]
Abstract
In men, prostate cancer (PC) is the most frequently diagnosed cancer, causing an estimated 375,000 deaths globally. Currently, existing therapies for the treatment of PC, notably metastatic cases, have limited efficacy due to drug resistance and problematic adverse effects. Therefore, it is imperative to discover and develop novel drugs for treating PC that are efficacious and do not produce intolerable adverse or toxic effects. Condensed quinolines are naturally occurring anticancer compounds. In this study, we determined the in vitro efficacy of IND-2 (4-chloro-2-methylpyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolone) in the PC lines, PC-3 and DU-145. IND-2 significantly inhibited the proliferation of PC-3 and DU-145, with IC50 values of 3 µM and 3.5 µM, respectively. The incubation of PC-3 cells with 5 and 10 µM of IND-2 caused the loss of the mitochondrial membrane potential in PC-3 cells. Furthermore, IND-2, at 5 µM, increased the expression of cleaved caspase-3, cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase (PARP). The incubation of PC-3 cells with 5 µM of IND-2 significantly decreased the expression of the apoptotic protein, B-cell lymphoma 2 (Bcl-2). Furthermore, 5 and 10 µM of IND-2 produced morphological changes in PC-3 cells characteristic of apoptosis. Interestingly, IND-2 (2.5, 5 and 10 µM) also induced mitotic catastrophe in PC-3 cells, characterized by the accumulation of multinuclei. The incubation of DU-145 cells with 1.25 and 5 μM of IND-2 significantly increased the levels of reactive oxygen species (ROS). Finally, IND-2, at 10 μM, inhibited the catalytic activity of topoisomerase IIα. Overall, our findings suggest that IND-2 could be a potential lead compound for the development of more efficacious compounds for the treatment of PC.
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Affiliation(s)
- Swapnaa Balaji
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Rabin Neupane
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Saloni Malla
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Rahul Khupse
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Findlay, Findlay, OH 43551, USA
| | - Haneen Amawi
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
- Department of Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan
| | - Shikha Kumari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Diwakar Bastihalli Tukaramrao
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Srestha Chattopadhyay
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Charles R. Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, St. John’s University, New York, NY 11432, USA
| | - Sai H. S. Boddu
- College of Pharmacy and Health Sciences, Ajman University, Ajman P.O. Box 346, United Arab Emirates
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Chandrabose Karthikeyan
- Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak 484887, Madhya Pradesh, India
| | - Piyush Trivedi
- Center for Innovation and Translational Research, Poona College of Pharmacy, Bharati Vidyapeeth, Pune 411038, Maharashtra, India
| | - Dayanidhi Raman
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Amit K. Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
- Correspondence: ; Tel.: +1-419-383-1913
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Tan CH, Sim DSY, Lim SH, Mohd Mohidin TB, Mohan G, Low YY, Kam TS, Sim KS. Antiproliferative and Microtubule-stabilizing Activities of Two Iboga-vobasine Bisindoles Alkaloids from Tabernaemontana corymbosa in Colorectal Adenocarcinoma HT-29 Cells. PLANTA MEDICA 2022; 88:1325-1340. [PMID: 35100653 DOI: 10.1055/a-1755-5605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the β-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.
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Affiliation(s)
- Chun Hoe Tan
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Dawn Su Yin Sim
- Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Siew Huah Lim
- Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Taznim Begam Mohd Mohidin
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Gokula Mohan
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Yun Yee Low
- Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Toh Seok Kam
- Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Kae Shin Sim
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
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23
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Krejbich P, Birringer M. The Self-Administered Use of Complementary and Alternative Medicine (CAM) Supplements and Antioxidants in Cancer Therapy and the Critical Role of Nrf-2-A Systematic Review. Antioxidants (Basel) 2022; 11:2149. [PMID: 36358521 PMCID: PMC9686580 DOI: 10.3390/antiox11112149] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 07/30/2023] Open
Abstract
Complementary and alternative medicine (CAM) supplements are widely used by cancer patients. Dietary supplements, vitamins and minerals, herbal remedies, and antioxidants are especially popular. In a systematic literature review, 37 studies, each including more than 1000 participants, on CAM, dietary supplement, and vitamin use among cancer patients were identified. Accordingly, cancer patients use antioxidants such as vitamin C (from 2.6% (United Kingdom) to 41.6% (United States)) and vitamin E (from 2.9% (China) to 48% (United States)). Dietary supplements and vitamins are taken for different reasons, but often during conventional cancer treatment involving chemotherapy or radiotherapy and in a self-decided manner without seeking medical advice from healthcare professionals. Drug-drug interactions with dietary supplements or vitamins involving multiple signaling pathways are well described. Since most of the anticancer drugs generate reactive oxygen species (ROS), an adaptive stress response of healthy and malignant cells, mainly driven by the Nrf-2-Keap I network, can be observed. On the one hand, healthy cells should be protected from ROS-overproducing chemotherapy and radiotherapy; on the other hand, ROS production in cancer cells is a "desirable side effect" during anticancer drug treatment. We here describe the paradoxical use of antioxidants and supplements during cancer therapy, possible interactions with anticancer drugs, and the involvement of the Nrf-2 transcription factor.
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Affiliation(s)
- Paula Krejbich
- Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
- Wissenschaftliches Zentrum für Ernährung, Lebensmittel und Nachhaltige Versorgungssysteme (ELVe), Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
- Public Health Zentrum Fulda, Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
| | - Marc Birringer
- Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
- Wissenschaftliches Zentrum für Ernährung, Lebensmittel und Nachhaltige Versorgungssysteme (ELVe), Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
- Public Health Zentrum Fulda, Fulda University of Applied Sciences, Leipziger Straße 123, 36037 Fulda, Germany
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24
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Ren S, Huang T, Ou D, Feng L, Huang S, Zhou C, Ge L. Inhibition of TNF- α and JNK Signaling Pathway Can Reduce Paclitaxel-Induced Apoptosis of Mouse Cardiomyocytes. Appl Bionics Biomech 2022; 2022:8460121. [PMID: 36016921 PMCID: PMC9398847 DOI: 10.1155/2022/8460121] [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: 06/22/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022] Open
Abstract
Paclitaxel (PTX) is a widely used chemotherapeutic drug for treating tumors. However, studies have shown that it can cause cardiac problems such as arrhythmia, myocarditis, chronic cardiomyopathy, and heart failure. Therefore, it is essential to study the mechanism behind the cardiotoxicity of PTX in tumor treatment. In this study, we initially injected PTX into mice to establish a myocardial cell apoptosis model to observe the degree of damage to mouse myocardium caused by PTX. Upon determining the levels of mouse myocardial creatine phosphokinase (CK), myokinase isoenzyme (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (LDH), we found that all of these levels showed apparent increases in mice treated with PTX. Further analyses of the TNF-α level and the expression of Jun N-terminal kinase (JNK) and Bcl-2 family-related proteins in myocardial tissue were performed. It was found that PTX increased the protein levels of TNF-α, Bax, p-JNK, and JNK in myocardial tissue but decreased the protein level of Bcl-2. After 1 month of PTX treatment in mice, we inhibited the expression of TNF-α and JNK proteins, which reduced the effect of paclitaxel on the apoptosis of mouse cardiomyocytes. The protein levels of Bax, p-JNK, and TNF-α in cardiomyocytes were reduced, while there was a relative increase in the Bcl-2 protein level. The findings suggested that inhibition of the NK signaling pathway and TNF-α can lessen the effect of PTX on mouse cardiomyocytes.
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Affiliation(s)
- Shuang Ren
- Department of General Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Tianwen Huang
- Department of Clinical Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Danyan Ou
- Department of General Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Luhuai Feng
- Department of General Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Sisi Huang
- Department of General Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Chaonan Zhou
- Department of General Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
| | - Lianying Ge
- Ultrasonic Department, Guangxi Medical University Cancer Hospital, Nanning, 530021 Guangxi, China
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25
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Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation. Int J Mol Sci 2022; 23:ijms23158248. [PMID: 35897820 PMCID: PMC9367815 DOI: 10.3390/ijms23158248] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 02/01/2023] Open
Abstract
This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.
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26
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Chaiswing L, Yarana C, St. Clair W, Tovmasyan A, Batinic-Haberle I, Spasojevic I, St. Clair D. A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP 5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9664636. [PMID: 35898616 PMCID: PMC9313984 DOI: 10.1155/2022/9664636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/29/2022] [Indexed: 12/20/2022]
Abstract
We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.
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Affiliation(s)
- Luksana Chaiswing
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA
| | | | - William St. Clair
- Department of Radiation Oncology, University of Kentucky, Kentucky, USA
| | - Artak Tovmasyan
- Translational Neuroscience at Barrow Neurological Institute, AZ, USA
| | | | - Ivan Spasojevic
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Pharmacokinetics/Pharmacodynamics Core Laboratory, Duke University School of Medicine, Durham, NC, USA
| | - Daret St. Clair
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA
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27
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Immune Responses in Leishmaniases: An Overview. Trop Med Infect Dis 2022; 7:tropicalmed7040054. [PMID: 35448829 PMCID: PMC9029249 DOI: 10.3390/tropicalmed7040054] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
Leishmaniasis is a parasitic, widespread, and neglected disease that affects more than 90 countries in the world. More than 20 Leishmania species cause different forms of leishmaniasis that range in severity from cutaneous lesions to systemic infection. The diversity of leishmaniasis forms is due to the species of parasite, vector, environmental and social factors, genetic background, nutritional status, as well as immunocompetence of the host. Here, we discuss the role of the immune system, its molecules, and responses in the establishment, development, and outcome of Leishmaniasis, focusing on innate immune cells and Leishmania major interactions.
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Chen S, Bian H, Duan J. High-Intensity Focused Ultrasound Enhanced Anti-Tumor Activities of Paclitaxel in Breast Cancer in vitro and in vivo. Cancer Manag Res 2022; 14:1303-1312. [PMID: 35386184 PMCID: PMC8978695 DOI: 10.2147/cmar.s349409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Background Paclitaxel (PTX) is an important oncologic chemotherapeutic agent against breast cancer, but breast cancer patients develop significant resistance to PTX during chemotherapy. Alterations in tubulin and associated proteins have been implicated in resistance to PTX. High-intensity focused ultrasound (HIFU) induces deep tumor penetration of anti-tumor agents in solid tumors. Methods We investigated the influence of HIFU on the anti-tumor activities of PTX in breast cancer. Both in vivo and in vitro experiments were performed in this research: mice were treated with 2 mg/Kg PTX through tail vein injection, while breast cancer cells were treated with 400 nM PTX. Cell viability was analyzed through Cell Counting Kit-8. Cell apoptosis was evaluated through Annexin-V/PI Apoptosis Analysis Kit. The activities of catalase (CAT) and superoxide dismutase (SOD) and the concentration of malondialdehyde (MDA) were evaluated by relative commercial kits. Results HIFU enhanced PTX-inhibited breast cancer cell viability and PTX-induced cell apoptosis. Simultaneous treatment of HIFU and PTX decreased the activities of CAT and SOD and increased the concentration of MDA. In mice bearing MDA-MB-231 tumors, the treatment of HIFU and PTX significantly decreased tumor size, increased body weight and elevated animal survival. HIFU enhanced the distribution of PTX in tumor tissues. Conclusion The performance of HIFU promoted the distribution of PTX and enhanced its anti-tumor activities in breast cancer.
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Affiliation(s)
- Sha Chen
- Department 2 of Ultrasound, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
- Correspondence: Sha Chen, Department 2 of Ultrasound, Cangzhou Central Hospital, No. 16, Xinhua West Road, Yunhe District, Cangzhou, 061000, Hebei, People’s Republic of China, Tel +86-18232858958, Email
| | - Hao Bian
- Magnetic Resonance Imaging Department, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
| | - Jingyu Duan
- Department 2 of Ultrasound, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
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Chatterjee A, Pal A, Paul S. A Novel Compound Plumercine from Plumeria alba Exhibits Promising Anti-Leukemic Efficacies against B Cell Acute Lymphoblastic Leukemia. Nutr Cancer 2022; 74:2565-2580. [PMID: 35102802 DOI: 10.1080/01635581.2021.2010777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The current study was focused to evaluate the antioxidant and the anti-cancerous properties of Plumeria alba. Plumeria alba was chosen due to its existing medicinal values. Antioxidant assays like Superoxide radical scavenging assay, Nitrous Oxide radical scavenging assay, were performed, on the methanolic and ethyl acetate extracts of the plant, that depicts the pro-oxidant nature of the extract. Further, they were tested to check cell viability on B cell Acute Lymphoblastic Leukemia (ALL) Cell line (NALM 6), human lung cancer cell line (A549), T cell Acute Lymphoblastic Leukemia cell line (MOLT4), and PBMC isolated from normal donors utilizing MTT assay. Robust anti-proliferative activity was observed in the case of NALM 6 followed by A549, MOLT4, whereas negligible activity was observed in the case of PBMC. Intrigued by this finding, in silico docking was performed using three bioactive compounds namely Plumericine, Isoplumericine, and 13-O-p-Coumaroylplumieride, unique to Plumeria sp. They were docked against five different cyclins and Cdk proteins responsible for ALL. The compounds have shown satisfactory results and their druggability and ADMET properties were checked further. Plumercine turned out to be the most competent compound and hence can be considered as a potential leukemic drug candidate in the future.
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Affiliation(s)
| | - Amrita Pal
- Department of Botany, University of Calcutta, Kolkata, India
| | - Santanu Paul
- Department of Botany, University of Calcutta, Kolkata, India
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Montero P, Milara J, Pérez-Leal M, Estornut C, Roger I, Pérez-Fidalgo A, Sanz C, Cortijo J. Paclitaxel-Induced Epidermal Alterations: An In Vitro Preclinical Assessment in Primary Keratinocytes and in a 3D Epidermis Model. Int J Mol Sci 2022; 23:ijms23031142. [PMID: 35163066 PMCID: PMC8834980 DOI: 10.3390/ijms23031142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Paclitaxel is a microtubule-stabilizing chemotherapeutic agent approved for the treatment of ovarian, non-small cell lung, head, neck, and breast cancers. Despite its beneficial effects on cancer and widespread use, paclitaxel also damages healthy tissues, including the skin. However, the mechanisms that drive these skin adverse events are not clearly understood. In the present study, we demonstrated, by using both primary epidermal keratinocytes (NHEK) and a 3D epidermis model, that paclitaxel impairs different cellular processes: paclitaxel increased the release of IL-1α, IL-6, and IL-8 inflammatory cytokines, produced reactive oxygen species (ROS) release and apoptosis, and reduced the endothelial tube formation in the dermal microvascular endothelial cells (HDMEC). Some of the mechanisms driving these adverse skin events in vitro are mediated by the activation of toll-like receptor 4 (TLR-4), which phosphorylate transcription of nuclear factor kappa B (NF-κb). This is the first study analyzing paclitaxel effects on healthy human epidermal cells with an epidermis 3D model, and will help in understanding paclitaxel's effects on the skin.
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Affiliation(s)
- Paula Montero
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
- Correspondence: (P.M.); (J.M.); Tel.: +34-963864631 (P.M.)
| | - Javier Milara
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain
- Pharmacy Unit, University General Hospital Consortium, 46014 Valencia, Spain
- Correspondence: (P.M.); (J.M.); Tel.: +34-963864631 (P.M.)
| | - Martín Pérez-Leal
- Faculty of Health Sciences, Universidad Europea de Valencia, 46010 Valencia, Spain;
| | - Cristina Estornut
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
| | - Inés Roger
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain
| | - Alejandro Pérez-Fidalgo
- Department of Medical Oncology, University Clinic Hospital of Valencia, 46010 Valencia, Spain;
- Biomedical Research Networking Centre on Cancer (CIBERONC), Health Institute Carlos III, 28029 Madrid, Spain
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | - Celia Sanz
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
- Health Sciences, Pre-Departmental Section of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.E.); (I.R.); (C.S.); (J.C.)
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain
- Research and Teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain
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Oyenihi OR, Oyenihi AB, Alabi TD, Tade OG, Adeyanju AA, Oguntibeju OO. Reactive oxygen species: Key players in the anticancer effects of apigenin? J Food Biochem 2022; 46:e14060. [PMID: 34997605 DOI: 10.1111/jfbc.14060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 01/04/2023]
Abstract
Reactive oxygen species (ROS) exhibit a double-edged sword in cancer-hence their modulation has been an attractive strategy in cancer prevention and therapy. The abundance of scientific information on the pro-oxidant effects of apigenin in cancer cells suggests the crucial role of ROS in its mechanisms of action. Although apigenin is known to enhance the cellular ROS levels to cytotoxic degrees in cancer cells in vitro, it remains to be determined if these pro-oxidant effects prevail or are relevant in experimental tumor models and clinical trials. Here, we critically examine the pro-oxidant and antioxidant effects of apigenin in cancer to provide insightful perspectives on the association between its ROS-modulating action and anticancer potential. We also discussed these effects in a cell/tissue type-specific context to highlight the factors influencing the switch between antioxidant and pro-oxidant effects. Finally, we raised some questions that need addressing for the potential translation of these studies into clinical applications. Further research into this duality in oxidant actions of apigenin, especially in vivo, may enable better exploitation of its anticancer potential. PRACTICAL APPLICATION: Apigenin is a naturally occurring compound found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. Many human trials of dietary interventions with apigenin-containing herbs and flavonoid mixture on oxidative stress markers, for instance, point to their antioxidant effects and health benefits in many diseases. Preclinical studies suggest that apigenin alone or its combination with chemotherapeutics has a strong anti-neoplastic effect and can induce ROS-mediated cytotoxicity at concentrations in the micromolar (μM) range, which may not be feasible with dietary interventions. Enhancing the in vivo pharmacokinetic properties of apigenin may be indispensable for its potential cancer-specific pro-oxidant therapy and may provide relevant information for clinical studies of apigenin either as a single agent or an adjuvant to chemotherapeutics.
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Affiliation(s)
- Omolola R Oyenihi
- Phytomedicine and Phytochemistry Group, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville, South Africa
| | - Ayodeji B Oyenihi
- Functional Foods Research Unit, Faculty of Applied Sciences, Cape Peninsula University of Technology, Bellville, South Africa
| | - Toyin D Alabi
- Phytomedicine and Phytochemistry Group, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville, South Africa
| | - Oluwatosin G Tade
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Anne A Adeyanju
- Department of Biological Sciences, Faculty of Applied Sciences, KolaDaisi University, Ibadan, Oyo State, Nigeria
| | - Oluwafemi O Oguntibeju
- Phytomedicine and Phytochemistry Group, Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville, South Africa
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Wu C, Wu T, Chen D, Wei S, Tang W, Xue L, Xiong J, Huang Y, Guo Y, Chen Y, Wu M, Wang S. The effects and mechanism of taxanes on chemotherapy-associated ovarian damage: A review of current evidence. Front Endocrinol (Lausanne) 2022; 13:1025018. [PMID: 36531475 PMCID: PMC9756165 DOI: 10.3389/fendo.2022.1025018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.
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Affiliation(s)
- Chuqing Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Tong Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Simin Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Weicheng Tang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Liru Xue
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yibao Huang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Yican Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Ying Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
- *Correspondence: Shixuan Wang, ; Meng Wu,
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
- *Correspondence: Shixuan Wang, ; Meng Wu,
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Asim S, Hussain A, Murad W, Hamayun M, Iqbal A, Rehman H, Tawab A, Irshad M, Alataway A, Dewidar AZ, Elansary HO, Lee IJ. Endophytic Fusarium oxysporum GW controlling weed and an effective biostimulant for wheat growth. FRONTIERS IN PLANT SCIENCE 2022; 13:922343. [PMID: 36003803 PMCID: PMC9394004 DOI: 10.3389/fpls.2022.922343] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/11/2022] [Indexed: 05/17/2023]
Abstract
Wheat crop has to compete with several weeds including Avena fatua, a noxious weed that alone is responsible for 30-70% losses in the yield annually. Because of the environmental concerns associated with conventional methods, researchers are on a continuous hunt to find clean alternatives in order to manage weeds. Fungi have shown promising weedicide potential in lab studies. The current study aimed to isolate endophytic fungi from wheat plants which can promote wheat growth and inhibit the growth of common weed, A. fatua. Of several isolates, GW (grayish white) was selected for its promising features, and the strain was identified as Fusarium oxisporum through ITS sequencing technique. This fungus released a number of compounds including Isovitexin, Calycosin, quercetagetin, and dihydroxy-dimethoxyisoflavone that inhibited the growth of A. fatua but did not influence the growth of wheat seedlings. Biomass of this fungus in the soil also reduced growth parameters of the weed and promoted the growth of wheat. For instance, the vigor index of A. fatua seedlings was reduced to only 6% of the control by this endophyte. In contrast, endophyte-associated wheat seedlings showed a higher vigor index than the control. Behind this differential response of the two plants were their contrasting physiological and biochemical status. Lower growth phenotypes of A. fatua seedlings had reduced levels of IAA, GAs, and SA and higher the levels of JA and ABA. Besides, their ROS scavenging ability was also compromised as evident from relatively lower activities of catalase, peroxidase, and ascorbic acid oxidase, as well as higher accumulation of ROS in their leaves. Wheat seedlings response to GW was opposite to the A. fatua. It may be concluded that F. oxysporum GW has the ability to differentially modulate physiology and biochemistry of the two hosts leading to contrasting phenotypic responses.
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Affiliation(s)
- Syed Asim
- Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Anwar Hussain
- Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
- *Correspondence: Anwar Hussain
| | - Waheed Murad
- Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Hamayun
- Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Amjad Iqbal
- Department of Food Science and Technology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Hazir Rehman
- Department of Microbiology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Abdul Tawab
- National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan
| | - Muhammad Irshad
- Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Abed Alataway
- Prince Sultan Bin Abdulaziz International Prize for Water Chair, Prince Sultan Institute for Environmental, Water and Desert Research, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Z. Dewidar
- Prince Sultan Bin Abdulaziz International Prize for Water Chair, Prince Sultan Institute for Environmental, Water and Desert Research, King Saud University, Riyadh, Saudi Arabia
- Department of Agricultural Engineering, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Hosam O. Elansary
- Plant Production Department, College of Food & Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - In-Jung Lee
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
- In-Jung Lee
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Aboelwafa H, Ramadan R, El-Kott A, Abdelhamid F. The protective effect of melatonin supplementation against taxol-induced testicular cytotoxicity in adult rats. Braz J Med Biol Res 2022; 55:e11614. [PMID: 35137851 PMCID: PMC8851920 DOI: 10.1590/1414-431x2021e11614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/30/2021] [Indexed: 01/22/2023] Open
Affiliation(s)
| | | | - A.F. El-Kott
- King Khalid University, Saudi Arabia; College of Science, Damanhour University, Egypt
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Meskers CJW, Franczak M, Smolenski RT, Giovannetti E, Peters GJ. Are we still on the right path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy. Expert Opin Drug Metab Toxicol 2022; 18:61-83. [PMID: 35238253 DOI: 10.1080/17425255.2022.2049234] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 01/18/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The pentose phosphate pathway (PPP) branches from glycolysis and is crucial for cell growth, since it provides necessary compounds for anabolic reactions, nucleotide synthesis, and detoxification of reactive-oxygen-species (ROS). Overexpression of PPP enzymes has been reported in multiple cancer types and linked to therapy resistance, making their inhibition interesting targets for anti-cancer therapies. AREAS COVERED This review summarizes the extent of PPP upregulation across different cancer types, and the non-metabolic functions that PPP-enzymes might contribute to cancer initiation and maintenance. The effects of PPP-inhibition and their combinations with chemotherapeutics are summarized. We searched the databases provided by the University of Amsterdam to characterize the altered expression of the PPP across different cancer types, and to identify the effects of PPP-inhibition. EXPERT OPINION It can be concluded that there are synergistic and additive effects of PPP-inhibition and various classes of chemotherapeutics. These effects may be attributed to the increased susceptibility to ROS. However, the toxicity, low efficacy, and off-target effects of PPP-inhibitors make application in clinical practice challenging. Novel inhibitors are currently being developed, which could make PPP-inhibition a potential therapeutic strategy in the future, especially in combination with conventional chemotherapeutics and the inhibition of other metabolic pathways.
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Affiliation(s)
- Caroline J W Meskers
- Amsterdam University College, Amsterdam, The Netherlands
- Laboratory Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam location VUMC, Cancer Center Amsterdam, The Netherlands
| | - Marika Franczak
- Department of Biochemistry, Medical University of Gdansk, Poland
| | | | - Elisa Giovannetti
- Laboratory Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam location VUMC, Cancer Center Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Godefridus J Peters
- Laboratory Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam location VUMC, Cancer Center Amsterdam, The Netherlands
- Department of Biochemistry, Medical University of Gdansk, Poland
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Lee G, Kim CW, Choi JR, Min KH, Lee HJ, Kwack KH, Lee HW, Lee JH, Jeong SY, Chang K, Lee SC. Copper arsenite-complexed Fenton-like nanoparticles as oxidative stress-amplifying anticancer agents. J Control Release 2021; 341:646-660. [PMID: 34921973 DOI: 10.1016/j.jconrel.2021.12.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 10/19/2022]
Abstract
We report copper(II) arsenite (CuAS)-integrated polymer micelles (CuAS-PMs) as a new class of Fenton-like catalytic nanosystem that can display reactive oxygen species (ROS)-manipulating anticancer therapeutic activity. CuAS-PMs were fabricated through metal-catechol chelation-based formation of the CuAS complex on the core domain of poly (ethylene glycol)-b-poly(3,4-dihydroxy-L-phenylalanine) (PEG-PDOPA) copolymer micelles. CuAS-PMs maintained structural robustness under serum conditions. The insoluble state of the CuAS complex was effectively retained at physiological pH, whereas, at endosomal pH, the CuAS complex was ionized to release arsenite and cuprous Fenton catalysts (Cu+ ions). Upon endocytosis, CuAS-PMs simultaneously released hydrogen peroxide (H2O2)-generating arsenite and Fenton-like reaction-catalyzing Cu+ ions in cancer cells, which synergistically elevated the level of highly cytotoxic hydroxyl radicals (•OH), thereby preferentially killing cancer cells. Animal experiments demonstrated that CuAS-PMs could effectively suppress the growth of solid tumors without systemic in vivo toxicity. The design rationale of CuAS-PMs may provide a promising strategy to develop diverse oxidative stress-amplifying agents with great potential in cancer-specific therapy.
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Affiliation(s)
- Giuk Lee
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Chan Woo Kim
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jeong Ryul Choi
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung Hyun Min
- Department of Pharmacy, School of Pharmacy, Jeonbuk National University, Jeonbuk 54896, Republic of Korea
| | - Hong Jae Lee
- Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyu Hwan Kwack
- Department of Pharmacology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeon-Woo Lee
- Department of Pharmacology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Hyung Lee
- Department of Oral Microbiology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seo Young Jeong
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kiyuk Chang
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
| | - Sang Cheon Lee
- Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea.
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Rad AT, Hargrove D, Daneshmandi L, Ramsdell A, Lu X, Nieh MP. Codelivery of Paclitaxel and Parthenolide in Discoidal Bicelles for a Synergistic Anticancer Effect: Structure Matters. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202100080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Armin Tahmasbi Rad
- Department of Biomedical Engineering University of Connecticut Storrs CT 06269 USA
- Polymer Program Institute of Materials Sciences University of Connecticut 191 Auditorium Road Storrs CT 06269 USA
- Encapsulate, University of Connecticut Technology Incubation Program Farmington CT 06032
| | - Derek Hargrove
- School of Pharmacy University of Connecticut Storrs CT 06269 USA
| | - Leila Daneshmandi
- Department of Biomedical Engineering University of Connecticut Storrs CT 06269 USA
- Encapsulate, University of Connecticut Technology Incubation Program Farmington CT 06032
| | - Amanda Ramsdell
- Department of Chemical and Bimolecular Engineering University of Connecticut Storrs CT 06269 USA
| | - Xiuling Lu
- Polymer Program Institute of Materials Sciences University of Connecticut 191 Auditorium Road Storrs CT 06269 USA
- School of Pharmacy University of Connecticut Storrs CT 06269 USA
| | - Mu-Ping Nieh
- Department of Biomedical Engineering University of Connecticut Storrs CT 06269 USA
- Polymer Program Institute of Materials Sciences University of Connecticut 191 Auditorium Road Storrs CT 06269 USA
- Department of Chemical and Bimolecular Engineering University of Connecticut Storrs CT 06269 USA
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Lan YY, Chen YH, Liu C, Tung KL, Wu YT, Lin SC, Wu CH, Chang HY, Chen YC, Huang BM. Role of JNK activation in paclitaxel-induced apoptosis in human head and neck squamous cell carcinoma. Oncol Lett 2021; 22:705. [PMID: 34457060 PMCID: PMC8358625 DOI: 10.3892/ol.2021.12966] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
It has been reported that paclitaxel activates cell cycle arrest and increases caspase protein expression to induce apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. However, the potential signaling pathway regulating this apoptotic phenomenon remains unclear. The present study used OEC-M1 cells to investigate the underlying molecular mechanism of paclitaxel-induced apoptosis. Following treatment with paclitaxel, cell viability was assessed via the MTT assay. Necrosis, apoptosis, cell cycle and mitochondrial membrane potential (∆Ψm) were analyzed via flow cytometric analyses, respectively. Western blot analysis was performed to detect the expression levels of proteins associated with the MAPK and caspase signaling pathways. The results demonstrated that low-dose paclitaxel (50 nM) induced apoptosis but not necrosis in HNSCC cells. In addition, paclitaxel activated the c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38 mitogen-activated protein kinase. The paclitaxel-activated JNK contributed to paclitaxel-induced apoptosis, activation of caspase-3, -6, -7, -8 and -9, and reduction of ∆Ψm. In addition, caspase-8 and -9 inhibitors, respectively, significantly decreased paclitaxel-induced apoptosis. Notably, Bid was truncated following treatment with paclitaxel. Taken together, the results of the present study suggest that paclitaxel-activated JNK is required for caspase activation and loss of ∆Ψm, which results in apoptosis of HNSCC cells. These results may provide mechanistic basis for designing more effective paclitaxel-combining regimens to treat HNSCC.
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Affiliation(s)
- Yu-Yan Lan
- Department of Physical Therapy, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C
| | - Ying-Hui Chen
- Department of Anesthesia, Chi-Mei Medical Center, Liouying, Tainan 73657, Taiwan, R.O.C
| | - Cheng Liu
- Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C.,Department of Health and Beauty, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C
| | - Kuo-Lung Tung
- Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C
| | - Yen-Ting Wu
- Department of Pathology, Golden Hospital, Pingtung 90049, Taiwan, R.O.C
| | - Sheng-Chieh Lin
- Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C
| | - Chin-Han Wu
- Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung 82144, Taiwan, R.O.C
| | - Hong-Yi Chang
- Department of Biotechnology and Food Technology, College of Engineering, Southern Taiwan University of Science and Technology, Tainan 71005, Taiwan, R.O.C
| | - Yung-Chia Chen
- Department of Anatomy, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Bu-Miin Huang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan, R.O.C.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
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βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies. Biochim Biophys Acta Rev Cancer 2021; 1876:188607. [PMID: 34364992 DOI: 10.1016/j.bbcan.2021.188607] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/21/2021] [Accepted: 08/02/2021] [Indexed: 12/30/2022]
Abstract
Class III β-tubulin (βIII-tubulin) is frequently overexpressed in human tumors and is associated with resistance to microtubule-targeting agents, tumor aggressiveness, and poor patient outcome. Understanding the mechanisms regulating βIII-tubulin expression and the varied functions βIII-tubulin may have in different cancers is vital to assess the prognostic value of this protein and to develop strategies to enhance therapeutic benefits in βIII-tubulin overexpressing tumors. Here we gather all the available evidence regarding the clinical implications of βIII-tubulin overexpression in cancer, describe factors that regulate βIII-tubulin expression, and discuss current understanding of the mechanisms underlying βIII-tubulin-mediated resistance to microtubule-targeting agents and tumor aggressiveness. Finally, we provide an overview of emerging therapeutic strategies to target tumors that overexpress βIII-tubulin.
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Neupane R, Malla S, Abou-Dahech MS, Balaji S, Kumari S, Waiker DK, Moorthy NSHN, Trivedi P, Ashby CR, Karthikeyan C, Tiwari AK. Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis. Molecules 2021; 26:molecules26154417. [PMID: 34361570 PMCID: PMC8347809 DOI: 10.3390/molecules26154417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/23/2021] [Accepted: 07/15/2021] [Indexed: 11/16/2022] Open
Abstract
A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.
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Affiliation(s)
- Rabin Neupane
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
| | - Saloni Malla
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
| | - Mariam Sami Abou-Dahech
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
| | - Swapnaa Balaji
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
| | - Shikha Kumari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
| | - Digambar Kumar Waiker
- School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal 462033, India;
| | | | - Piyush Trivedi
- Center of Innovation and Translational Research, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune 411030, India;
| | - Charles R. Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy, St. John’s University, Queens, NY 11439, USA;
| | - Chandrabose Karthikeyan
- Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak 484887, India;
- Correspondence: (C.K.); (A.K.T.); Tel.: +91-7587521152 (C.K.); +1-419-383-1913 (A.K.T.); Fax: +1-419-383-1909 (A.K.T.)
| | - Amit K. Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA; (R.N.); (S.M.); (M.S.A.-D.); (S.B.); (S.K.)
- Department Centre of Medical and Bio-allied Health Sciences Research (CMBHSR), Ajman University, Ajman P.O. Box 346, United Arab Emirates
- Department of Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA
- Correspondence: (C.K.); (A.K.T.); Tel.: +91-7587521152 (C.K.); +1-419-383-1913 (A.K.T.); Fax: +1-419-383-1909 (A.K.T.)
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Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021; 22:ijms22073765. [PMID: 33916438 PMCID: PMC8038573 DOI: 10.3390/ijms22073765] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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Thiagarajan K, Mohan S, Roy TK, Chandrasekaran R. Antiproliferative effect of Acacia nilotica (L.) leaf extract rich in ethyl gallate against human carcinoma cell line KB. Indian J Pharmacol 2021; 52:488-494. [PMID: 33666190 PMCID: PMC8092180 DOI: 10.4103/ijp.ijp_223_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVES The objective of this study is to analyze the antiproliferative activity of Acacia nilotica (L.) leaf ethanolic extract against cancer KB cells and to determine the mode of cancer cytotoxicity. MATERIALS AND METHODS In this study, high-performance liquid chromatography and liquid chromatography-mass spectrometry analysis were done to confirm the presence of ethyl gallate as a major bioactive phenolic in the leaf ethanolic extract of A. nilotica, further dose-dependent (0-120 μg/mL) antiproliferative effect was investigated in human carcinoma cell line KB. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, reactive oxygen species, mitochondrial membrane potential loss, DNA damage, and apoptosis were evaluated. RESULTS A. nilotica leaf ethanolic extract (ANLEE) showed effective concentration (EC50) of 40 μg/mL. Interference of growth was significantly (P < 0.05) high in KB cells treated with ANLEE when compared to untreated control, but less when compared to the reference drug paclitaxel. In addition, the in vivo acute toxicity study demonstrated the safe limit of administration of 2000 mg/kg body weight ANLEE by the histological analysis in rats. The results from the present study indicate that mitochondria and DNA of KB cells are severely affected leading to apoptosis. CONCLUSIONS ANLEE is a prospective source for cancer therapy and therefore should be highlighted to explore on its wide range of safety in rats and efficacy against human carcinoma cell line KB.
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Affiliation(s)
- Kalaivani Thiagarajan
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Shalini Mohan
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Tapas Kumar Roy
- Division of Plant Physiology and Biochemistry, Indian Institute of Horticultural Research, Bengaluru, Karnataka, India
| | - Rajasekaran Chandrasekaran
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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Targeting Nrf2 may reverse the drug resistance in ovarian cancer. Cancer Cell Int 2021; 21:116. [PMID: 33596893 PMCID: PMC7890806 DOI: 10.1186/s12935-021-01822-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/06/2021] [Indexed: 12/11/2022] Open
Abstract
Background Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. Main Body Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. Conclusions Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.
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Abdel Hadi N, Reyes-Castellanos G, Carrier A. Targeting Redox Metabolism in Pancreatic Cancer. Int J Mol Sci 2021; 22:ijms22041534. [PMID: 33546421 PMCID: PMC7913542 DOI: 10.3390/ijms22041534] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 12/12/2022] Open
Abstract
Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic.
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Affiliation(s)
| | | | - Alice Carrier
- Correspondence: ; Tel.: +33-491-828-829; Fax: +33-491-826-083
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Poluboyarinov PA, Elistratov DG, Moiseeva IJ. Antitumor Activity of Selenium and Search Parameters for Its New Potentially Active Derivatives. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162020060254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Evaluation of the anticancer activity of enzymatically synthesized Baccatin III: an intermediate precursor of Taxol®. 3 Biotech 2020; 10:465. [PMID: 33088661 DOI: 10.1007/s13205-020-02457-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/27/2020] [Indexed: 01/05/2023] Open
Abstract
Baccatin III is an important precursor for the synthesis of clinically important anticancer drug Taxol. Previously, we have characterized a key enzyme of 10-deacetylbaccatin III-10-β-O-acetyltransferase (DBAT) which catalyses the 10-deacetylbaccatin III into baccatin III in taxol biosynthesis. Here, in the present study, we have evaluated and compared the cytotoxic properties of the enzymatically synthesized baccatin III (ESB III) with standard baccatin III in different human cancer cell lines, namely human cervical cancer (HeLa), human lung cancer (A549), human skin cancer (A431) and human liver cancer cells (HepG2). Among the various cancer lines tested, HeLa was more susceptible to ESB III with IC50 of 4.30 µM while IC50 values for A549, A431 and HepG2 ranged from 4 to 7.81 µM. Further, it showed G2/M phase cell cycle arrest, production of reactive oxygen species and depolarised mitochondrial membrane potential. In addition, annexin V-FITC staining was performed which showed the apoptotic cell death of HeLa cells, when treated with ESB III. Hence, ESB III was capable to show anticancer activities by inducing apoptotic cell death which could further be used for the semisynthesis of taxol in future.
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Majumder D, Nath P, Debnath R, Maiti D. Understanding the complicated relationship between antioxidants and carcinogenesis. J Biochem Mol Toxicol 2020; 35:e22643. [PMID: 32996240 DOI: 10.1002/jbt.22643] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 07/09/2020] [Accepted: 09/17/2020] [Indexed: 12/11/2022]
Abstract
Reactive oxygen species (ROS) are generated as by-product of cellular respiration and also due to the exposure of various xenobiotics, whereas mitochondrial electron transport chain is considered as the main source of ROS generation. The sequential addition to molecular oxygen gives rise to various forms of ROS like superoxide anion, peroxide, hydroxyl radical, hydroxyl ion, and so forth. However, the uncontrolled level of ROS generation and accumulation alters the body homeostasis. Excessive generation of ROS leads to oxidative stress and various kinds of diseases including cancer. To counteract ROS, enzymatic and nonenzymatic antioxidants' armory is available in our body. Apart from endogenous antioxidants, we are also consuming various exogenous antioxidants. Antioxidants protect us from ROS-mediated damages and inhibit ROS-induced carcinogenesis. Recent studies have revealed that antioxidants could also act as tumor-promoting agents. Various anticancer drugs are used to kill the cancer cells through the generation of oxidative stress in them, but the cancer cells can counteract the effect with the help of various endogenous as well as exogenous antioxidants. Our review will summarize the multifaceted relationship between antioxidants and carcinogenesis, and it will help to create new directions in antioxidant-based chemotherapy.
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Affiliation(s)
- Debabrata Majumder
- Department of Human Physiology, Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Priyatosh Nath
- Department of Human Physiology, Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Rahul Debnath
- Department of Human Physiology, Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Debasish Maiti
- Department of Human Physiology, Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
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Ueda S, Takanashi M, Sudo K, Kanekura K, Kuroda M. miR-27a ameliorates chemoresistance of breast cancer cells by disruption of reactive oxygen species homeostasis and impairment of autophagy. J Transl Med 2020; 100:863-873. [PMID: 32066826 DOI: 10.1038/s41374-020-0409-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
In patients with breast cancer, primary chemotherapy often fails due to survival of chemoresistant breast cancer stem cells (BCSCs) which results in recurrence and metastasis of the tumor. However, the factors determining the chemoresistance of BCSCs have remained to be investigated. Here, we profiled a series of differentially expressed microRNAs (miRNAs) between parental adherent breast cancer cells and BCSC-mimicking mammosphere-derived cancer cells, and identified hsa-miR-27a as a negative regulator for survival and chemoresistance of BCSCs. In the mammosphere, we found that the expression of hsa-miR-27a was downregulated, and ectopic overexpression of hsa-miR-27a reduced both number and size of mammospheres. In addition, overexpression of hsa-miR-27a sensitized breast cancer cells to anticancer drugs by downregulation of genes essential for detoxification of reactive oxygen species (ROS) and impairment of autophagy. Therefore, enhancing the hsa-miR-27a signaling pathway can be a potential therapeutic modality for breast cancer.
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Affiliation(s)
- Shinobu Ueda
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Masakatsu Takanashi
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Katsuko Sudo
- Preclinical Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Kohsuke Kanekura
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
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LHRH-conjugated, PEGylated, poly-lactide-co-glycolide nanocapsules for targeted delivery of combinational chemotherapeutic drugs Docetaxel and Quercetin for prostate cancer. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 114:111035. [PMID: 32994029 DOI: 10.1016/j.msec.2020.111035] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/26/2022]
Abstract
One of the major challenges in effective cancer chemotherapy is the severe systemic cytotoxicities of anticancer drugs on healthy tissues. The present study reports chemically modified polymeric nanocapsules (NCs) encapsulating combination of chemotherapeutic drugs Docetaxel (DTX) and Quercetin (QU) for its active targeting to prostate cancer (PCa). The active targeting was achieved by conjugating Luteinizing-hormone-releasing hormone (LHRH) ligand to poly-lactide-co-glycolide (PLGA) using polyethylene glycol (PEG) as a spacer. The structure of the conjugates was characterized and confirmed using 1H NMR and ATR-FTIR. The drug encapsulated NCs showed a homogenous size distribution with their size ranging between 120 and 150 nm, and exhibited a negative zeta potential in the range of -20 to -40 mV. The in vitro release studies highlighted the sustained drug release pattern from the respective NCs; while the PEG coating to polymeric NCs provided serum stability to the NCs. The in vitro biological evaluation of the NCs was conducted using PC-3 and LNCaP cell lines. The results of the cellular uptake studies showed a significantly higher untake of the LHRH targeted NCs, while the LHRH-targeted-PEGylated DTX: QU NCs exhibited higher caspase-3 activity. The cell viability assay results showed the enhanced cell inhibition activity of the combinatorial DTX: QU when compared to individual DTX. Further, higher cell cytotoxicity was achieved by LHRH-targeted DTX: QU NCs as compared to their free-form or non-targeted NCs. Finally, the results of in vivo tumor localization and in vivo antitumor activity studies complimented and upheld the in vitro results, demonstrating the beneficial role of PLGA-PEG-LHRH NCs encapsulating combination of DTX and QU in combating prostate cancer (PCa).
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An H, Guo C, Li D, Liu R, Xu X, Guo J, Ding J, Li J, Chen W, Zhang J. Hydrogen Peroxide-Activatable Nanoparticles for Luminescence Imaging and In Situ Triggerable Photodynamic Therapy of Cancer. ACS APPLIED MATERIALS & INTERFACES 2020; 12:17230-17243. [PMID: 32193923 DOI: 10.1021/acsami.0c01413] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Abnormally increased reactive oxygen species (ROS) are intimately related to the development and metastasis of cancer. Since hydrogen peroxide (H2O2) is a major component of ROS, molecular imaging and selective treatment in response to high H2O2 are intriguing for the management of cancers. Herein, we report novel self-assembly luminescent nanoparticles, which can be activated by H2O2, thereby serving as an effective nanotheranostics for luminescence imaging and in situ photodynamic therapy (PDT) of tumors with high H2O2. This functional nanomedicine was assembled from an amphiphilic conjugate (defined as CLP) based on chlorin e6 (Ce6) simultaneously conjugated with luminol and poly(ethylene glycol), exhibiting a well-defined core-shell nanostructure. Upon triggering by pathologically relevant levels of H2O2, CLP nanoparticles produced luminescence due to the luminol unit and simultaneous excitation of Ce6 by chemiluminescence resonance energy transfer, enabling in vitro and in vivo imaging of tumors with highly expressed H2O2. In addition, excited Ce6 can produce singlet oxygen (1O2) for in situ PDT of H2O2-high tumors and inhibiting lung metastasis, which was demonstrated by in vitro and in vivo experiments. Furthermore, preliminary studies revealed the biosafety of CLP nanoparticles. Consequently, the self-illuminating nanoparticles are promising for noninvasive imaging and therapy of tumors with high expression of H2O2.
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Affiliation(s)
- Huijie An
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Department of Pharmacy, General Hospital of Southern Theatre Command, PLA, Guangzhou 510010, China
| | - Chunhua Guo
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Dandan Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Renfeng Liu
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xiaoqiu Xu
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jiawei Guo
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jun Ding
- Department of Ultrasound, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jianjun Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Wei Chen
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jianxiang Zhang
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
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