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Falsetti I, Palmini G, Zonefrati R, Vasa K, Donati S, Aurilia C, Baroncelli A, Viglianisi C, Ranaldi F, Iantomasi T, Procacci P, Menichetti S, Brandi ML. Antiproliferative Role of Natural and Semi-Synthetic Tocopherols on Colorectal Cancer Cells Overexpressing the Estrogen Receptor β. Int J Mol Sci 2025; 26:2305. [PMID: 40076925 PMCID: PMC11900421 DOI: 10.3390/ijms26052305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Estrogen receptor β (ERβ) is the most highly expressed subtype in the colon epithelium and mediates the protective effect of estrogen against the development of colon cancer. Indeed, the expression of this receptor is inversely related to colorectal cancer progression. Structurally estrogen-like compounds, including vitamin E components, affect cell growth by binding to ERs. In the present study, cell proliferation was measured by cell counting in a Bürker hemocytometer, and ERβ expression was measured by Real-Time qPCR and immunoenzymatic methods. The results obtained show that natural δ-tocopherol (δ-Toc) and two of its semi-synthetic derivatives, bis-δ-tocopheryl sulfide (δ-Toc)2S and bis-δ-tocopheryl disulfide (δ-Toc)2S2, play an antiproliferative role and upregulate ERβ expression, similar to 17-β-estradiol (17β-E2), in human colon adenocarcinoma HCT8 cells engineered to overexpress ERβ protein (HCT8-β8). These events are not present in HCT8-pSV2neo and in HCT8-β8 pretreated with ICI 182,780, suggesting that they are mediated by the binding of compounds to ERβ, as also boosted by an in silico assay. The antiproliferative effect is independent of the intracellular redox state and (δ-Toc)2S and (δ-Toc)2S2 reduce cell proliferation at concentrations lower than that of δ-Toc and all tested compounds are also able to upregulate ERβ expression. Taken together, the data indicate that, through the involvement of ERβ activity and expression, δ-Toc, (δ-Toc)2S, and (δ-Toc)2S2 may provide potential therapeutic support against colorectal cancer.
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Affiliation(s)
- Irene Falsetti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy; (I.F.); (S.D.); (C.A.); (F.R.)
| | - Gaia Palmini
- Italian Foundation for Research on Bone Disease (F.I.R.M.O.), Via San Gallo 123, 50129 Firenze, Italy; (G.P.); (M.L.B.)
| | - Roberto Zonefrati
- Italian Foundation for Research on Bone Disease (F.I.R.M.O.), Via San Gallo 123, 50129 Firenze, Italy; (G.P.); (M.L.B.)
| | - Kristian Vasa
- Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia, 3–13, 50019 Sesto Fiorentino, Italy; (K.V.); (A.B.); (C.V.); (P.P.); (S.M.)
| | - Simone Donati
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy; (I.F.); (S.D.); (C.A.); (F.R.)
| | - Cinzia Aurilia
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy; (I.F.); (S.D.); (C.A.); (F.R.)
| | - Allegra Baroncelli
- Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia, 3–13, 50019 Sesto Fiorentino, Italy; (K.V.); (A.B.); (C.V.); (P.P.); (S.M.)
| | - Caterina Viglianisi
- Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia, 3–13, 50019 Sesto Fiorentino, Italy; (K.V.); (A.B.); (C.V.); (P.P.); (S.M.)
| | - Francesco Ranaldi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy; (I.F.); (S.D.); (C.A.); (F.R.)
| | - Teresa Iantomasi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy; (I.F.); (S.D.); (C.A.); (F.R.)
| | - Piero Procacci
- Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia, 3–13, 50019 Sesto Fiorentino, Italy; (K.V.); (A.B.); (C.V.); (P.P.); (S.M.)
| | - Stefano Menichetti
- Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia, 3–13, 50019 Sesto Fiorentino, Italy; (K.V.); (A.B.); (C.V.); (P.P.); (S.M.)
| | - Maria Luisa Brandi
- Italian Foundation for Research on Bone Disease (F.I.R.M.O.), Via San Gallo 123, 50129 Firenze, Italy; (G.P.); (M.L.B.)
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Ma G, Chong W, Qi Y, Lu Z, Zhang Z, Nian B, Hu Y. Can vitamin E ester derivatives be excellent alternatives of vitamin E: state of art. Bioprocess Biosyst Eng 2023; 46:1695-1709. [PMID: 37555945 DOI: 10.1007/s00449-023-02918-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/27/2023] [Indexed: 08/10/2023]
Abstract
Vitamin E (VE) is a natural antioxidant which is widely used in the food fields, while the shortcomings of easy oxidative inactivation and poor water solubility limit its application. Vitamin E esters' (VEEs) derivatives, such as vitamin E acetate (VEA), are more stable and easier to be absorbed while have similar biological activities and physiological functions compared with VE. In this systematic review, the digestion, absorption and physiological function of VEEs were summarized. To promote their further industrial applications, the synthesis strategies of VEEs were also summarized in-depth. In particular, as a new generation of green solvents, ionic liquids (ILs) have been widely used in enzymatic reactions due to the stabilization and activation of enzymes. Their applications in enzymatic synthesis of VEEs were summarized and discussed. Finally, several future perspectives for developing more efficiency strategies of VEEs synthesis, such as enzyme engineering and design of novel ILs, were also discussed.
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Affiliation(s)
- Guangzheng Ma
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Wenya Chong
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Yuan Qi
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Zeping Lu
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Zihan Zhang
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Binbin Nian
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China.
| | - Yi Hu
- State Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, Jiangsu Province, People's Republic of China.
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Prasad KN. Discovery of Alpha-Tocopheryl Succinate as a Cancer Treatment Agent Led to the Development of Methods to Potentially Improve the Efficacy of Cancer Therapy. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2023; 42:776-782. [PMID: 36735863 DOI: 10.1080/27697061.2023.2175389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/28/2023] [Indexed: 02/05/2023]
Abstract
The discovery of alpha-tocopheryl succinate (alpha-TS) as a cancer therapeutic agent markedly stimulated research with or without tumor therapeutic agents on cancer cells and normal cells. Results showed that alpha-TS treatment induced apoptosis in cancer cells and enhanced the apoptotic effects of tumor therapeutic agents on tumor cells in a synergistic manner without affecting the growth of normal cells. Liposomal alpha-TS was more effective than alpha-TS. Some tumors are difficult to treat with chemotherapeutic agents while some become resistant of such treatment. Using a nanotechnology technique, it was demonstrated that alpha-TS conjugated with a chemotherapeutic agent enhanced the levels of apoptosis and restored the sensitivity of tumor cells to that chemotherapeutic agent. The mechanisms of action of alpha-TS alone or in combination with therapeutic agents include the following: (a) inhibition of the expression of oncogenes C-myc and H-ras; (b) alterations in the levels of expression of numerous genes; (c) activation of caspases; (d) inhibition of angiogenesis; (e) destabilization of mitochondria and lysosomes; (f) inhibition of production of production of prostaglandin E2 (PGE2) and PGE2-mediated pro-inflammatory responses; (g) reduction of survivin signaling pathway; and (h) reduction of CD47 expression on the tumor cell surface causing enhancement of phagocytic activity of macrophages leading to engulfment of tumor cells. Despite impressive results in cell culture and in animal models, no studies with alpha-TS alone or in combination with cancer therapeutic agents in human cancer resistant to these therapies have been performed.
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Taniguchi S, Ono Y, Doi Y, Taniguchi S, Matsuura Y, Iwasaki A, Hirata N, Fukuda R, Inoue K, Yamaguchi M, Tashiro A, Egami D, Aoki S, Kondoh Y, Honda K, Osada H, Kumeta H, Saio T, Okiyoneda T. Identification of α-Tocopherol succinate as an RFFL-substrate interaction inhibitor inducing peripheral CFTR stabilization and apoptosis. Biochem Pharmacol 2023; 215:115730. [PMID: 37543348 DOI: 10.1016/j.bcp.2023.115730] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/06/2023] [Accepted: 07/31/2023] [Indexed: 08/07/2023]
Abstract
The E3 ubiquitin ligase RFFL is an apoptotic inhibitor highly expressed in cancers and its knockdown suppresses cancer cell growth and sensitizes to chemotherapy. RFFL also participates in peripheral protein quality control which removes the functional cell surface ΔF508-CFTR channel and reduces the efficacy of pharmaceutical therapy for cystic fibrosis (CF). Although RFFL inhibitors have therapeutic potential for both cancer and CF, they remain undiscovered. Here, a chemical array screening has identified α-tocopherol succinate (αTOS) as an RFFL ligand. NMR analysis revealed that αTOS directly binds to RFFL's substrate-binding region without affecting the E3 enzymatic activity. Consequently, αTOS inhibits the RFFL-substrate interaction, ΔF508-CFTR ubiquitination and elimination from the plasma membrane of epithelial cells, resulting in the increased functional CFTR channel. Among the α-tocopherol (αTOL) analogs we tested, only αTOS inhibited the RFFL-substrate interaction and increased the cell surface ΔF508-CFTR, depending on RFFL expression. Similarly, the unique proapoptotic effect of αTOS was dependent on RFFL expression. Thus, unlike other αTOL analogs, αTOS acts as an RFFL protein-protein interaction inhibitor which may explain its unique biological properties among αTOL analogs. Moreover, αTOS may act as a CFTR stabilizer, a novel class of drugs that extend cell surface ΔF508-CFTR lifetime.
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Affiliation(s)
- Sachiho Taniguchi
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Yuji Ono
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Yukako Doi
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Shogo Taniguchi
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Yuta Matsuura
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Ayuka Iwasaki
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Noriaki Hirata
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Ryosuke Fukuda
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
| | - Keitaro Inoue
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan
| | - Miho Yamaguchi
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan
| | - Anju Tashiro
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan
| | - Daichi Egami
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan
| | - Shunsuke Aoki
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan
| | - Yasumitsu Kondoh
- Chemical Resource Development Unit, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan
| | - Kaori Honda
- Chemical Resource Development Unit, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan
| | - Hiroyuki Osada
- Chemical Resource Development Unit, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan
| | - Hiroyuki Kumeta
- Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido 060-0810, Japan
| | - Tomohide Saio
- Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
| | - Tsukasa Okiyoneda
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan.
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Yu H, Zaveri S, Sattar Z, Schaible M, Perez Gandara B, Uddin A, McGarvey LR, Ohlmeyer M, Geraghty P. Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1552. [PMID: 37763671 PMCID: PMC10535831 DOI: 10.3390/medicina59091552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023]
Abstract
New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.
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Affiliation(s)
- Howard Yu
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Sahil Zaveri
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Zeeshan Sattar
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Michael Schaible
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Brais Perez Gandara
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Anwar Uddin
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | - Lucas R. McGarvey
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
| | | | - Patrick Geraghty
- Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; (H.Y.); (S.Z.); (Z.S.); (M.S.); (B.P.G.); (A.U.); (L.R.M.)
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Khallouki F, Hajji L, Saber S, Bouddine T, Edderkaoui M, Bourhia M, Mir N, Lim A, El Midaoui A, Giesy JP, Aboul-Soud MAM, Silvente-Poirot S, Poirot M. An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management. J Pers Med 2023; 13:jpm13050754. [PMID: 37240924 DOI: 10.3390/jpm13050754] [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: 04/08/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.
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Affiliation(s)
- Farid Khallouki
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Lhoussain Hajji
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Somayya Saber
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Toufik Bouddine
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Mouad Edderkaoui
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center & University of California, Los Angeles, CA 90048, USA
| | - Mohammed Bourhia
- Higher Institute of Nursing Professions and Technical Health, Laayoune 70000, Morocco
| | - Nora Mir
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Adrian Lim
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center & University of California, Los Angeles, CA 90048, USA
| | - Adil El Midaoui
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
| | - John P Giesy
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada
- Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
- Department of Integrative Biology, Michigan State University, East Lansing, MI 48824, USA
- Department of Environmental Sciences, Baylor University, Waco, TX 76706, USA
| | - Mourad A M Aboul-Soud
- Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | - Sandrine Silvente-Poirot
- Cancer Research Center of Toulouse, UMR 1037 INSERM, UMR 5071 CNRS, University of Toulouse III, Equipe labellisée par la Ligue Nationale Contre le Cancer, 31037 Toulouse, France
- French Network for Nutrition And Cancer Research (NACRe Network), 78350 Jouy-en-Josas, France
| | - Marc Poirot
- Cancer Research Center of Toulouse, UMR 1037 INSERM, UMR 5071 CNRS, University of Toulouse III, Equipe labellisée par la Ligue Nationale Contre le Cancer, 31037 Toulouse, France
- French Network for Nutrition And Cancer Research (NACRe Network), 78350 Jouy-en-Josas, France
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Mondal SK, Jinka S, Shankar G, Srinivas R, Banerjee R. Modification of α-Tocopherol Succinate with a Tumor-targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel-loaded Lipid Aggregate. Chem Asian J 2023; 18:e202201136. [PMID: 36482874 DOI: 10.1002/asia.202201136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022]
Abstract
Paclitaxel (PTX) is a widely used chemotherapeutic agent in the clinic. However, its clinical benefit is limited due to its low water solubility, off-target toxicity, and for being a multidrug-resistant (MDR) substrate. To overcome these limitations in this study, a tumor-targeting peptide (CRGDK peptide, a ligand for NRP-1 receptor) conjugate of α-tocopheryl succinate (α-TOS) was synthesized and modified on PTX-loaded lipid aggregate (TL-PTX) to leverage the benefits of α-TOS, which include a) anti-cancer activity, b) increased PTX loading, and c) inhibition of MDR activity. Use of peptide conjugate of α-TOS (α-TOS-CRGDK) in lipid aggregate increased PTX entrapment efficiency by 20%, helped in NRP-1 specific cellular uptake and significantly enhanced apoptotic and cell killing activity (p <0.01) of PTX compared to control formulation (CL-PTX) by inhibiting MDR-activity in melanoma resulting in ∼70% increment in overall survival of melanoma tumor-bearing mice. In conclusion, CRGDK- α-TOS conjugate in association with PTX-loaded liposome provided a unique NRP-1 targeted, drug-resistant reversing anticancer regimen for treating aggressive melanoma.
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Affiliation(s)
- Sujan Kumar Mondal
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, India
- Department of Radiology, Michigan State University, East Lansing, Michigan (USA
| | - Sudhakar Jinka
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, India
- Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Gajji Shankar
- Mass Spectrometry Division, CSIR - Indian Institute of Chemical Technology (CSIRIICT), Uppal Road, Tarnaka, Hyderabad, 500 007, Telangana State, India
| | - Ragampeta Srinivas
- Mass Spectrometry Division, CSIR - Indian Institute of Chemical Technology (CSIRIICT), Uppal Road, Tarnaka, Hyderabad, 500 007, Telangana State, India
| | - Rajkumar Banerjee
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, India
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8
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Kashani E, Vassella E. Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype. Cancers (Basel) 2022; 14:5227. [PMID: 36358647 PMCID: PMC9654311 DOI: 10.3390/cancers14215227] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/13/2022] [Accepted: 10/20/2022] [Indexed: 07/29/2023] Open
Abstract
Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on "glioblastoma, IDH wild-type" (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.
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Affiliation(s)
- Elham Kashani
- Institute of Pathology, University of Bern, 3008 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Erik Vassella
- Institute of Pathology, University of Bern, 3008 Bern, Switzerland
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Effect of α-Tocopheryloxy Acetic Acid on the Infection of Mice with Plasmodium berghei ANKA In Vivo and Humans with P. falciparum In Vitro. Acta Parasitol 2022; 67:1514-1520. [PMID: 35951222 DOI: 10.1007/s11686-022-00604-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/21/2022] [Indexed: 11/01/2022]
Abstract
PURPOSE Malarial parasites are susceptible to oxidative stress. The effects of α-tocopheryloxy acetic acid (α-TEA), a vitamin E analog, on infection by Plasmodium berghei ANKA and P. falciparum in mice and human red blood cells (RBCs), respectively, were examined in this study. METHODS For in vivo studies in mice, RBCs infected with P. berghei ANKA were inoculated via intraperitoneal injection and α-TEA was administered to C57BL/6 J male mice after infection. The blood-brain barrier (BBB) permeability was examined by Evans blue staining in experimental cerebral malaria at 7 days after infection. The in vitro inhibitory effect of α-TEA on P. falciparum 3D7 (chloroquine-sensitive strain) and K1 (multidrug-resistant strain) was tested using a SYBR Green I-based assay. RESULTS When 1.5% α-TEA was administered for 14 days after infection, 88% of P. berghei ANKA-infected mice survived during the experimental period. Nevertheless, all the control mice died within 12 days of infection. Furthermore, the Evans blue intensity in α-TEA-treated mice brains was less than that in untreated mice, indicating that α-TEA might inhibit the destruction of the BBB and progression of cerebral malaria. The in vitro experiment revealed that α-TEA inhibited the proliferation of both the 3D7 and K1 strains. CONCLUSION This study showed that α-TEA is effective against murine and human malaria in vivo and in vitro, respectively. Although α-TEA alone has a sufficient antimalarial effect, future research could focus on the structure-activity relationship to achieve better pharmacokinetics and decrease the cytotoxicity and/or the combined effect of α-TEA with existing drugs. In addition, the prophylactic antimalarial activity of premedication with α-TEA may also be an interesting perspective in the future.
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10
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Pan J, Zhou L, Zhang C, Xu Q, Sun Y. Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy. Signal Transduct Target Ther 2022; 7:177. [PMID: 35665742 PMCID: PMC9166240 DOI: 10.1038/s41392-022-01038-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/28/2022] [Accepted: 05/25/2022] [Indexed: 11/09/2022] Open
Abstract
Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the "double-edged sword" function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.
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Affiliation(s)
- Jie Pan
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Lisha Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Chenyang Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China.
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
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Liu Y, Zhang J, Tu Y, Zhu L. Potential-Independent Intracellular Drug Delivery and Mitochondrial Targeting. ACS NANO 2022; 16:1409-1420. [PMID: 34920667 PMCID: PMC9623822 DOI: 10.1021/acsnano.1c09456] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
In this study, two types of the fluoroamphiphile analogs were synthesized and self-assembled into the "core-shell" micellar nanocarriers for intracellular delivery and organelle targeting. Using the fluorescent dyes or vitamin E succinate as the cargo, the drug delivery and targeting capabilities of the fluoroamphiphiles and their micelles were evaluated in the cell lines, tumor cell spheroids, and tumor-bearing mice. The "core-fluorinated" micelles exhibited favorable physicochemical properties and improved the cellular uptake of the cargo by around 20 times compared to their "shell-fluorinated" counterparts. The results also indicated that the core-fluorinated micelles underwent an efficient clathrin-mediated endocytosis and a rapid endosomal escape thereafter. Interestingly, the internalized fluoroamphiphile micelles preferentially accumulated in mitochondria, by which the efficacy of the loaded vitamin E succinate was boosted both in vitro and in vivo. Unlike the popularly used cationic mitochondrial targeting ligands, as a charge-neutral nanocarrier, the fluoroamphiphiles' mitochondrial targeting was potential independent. The mechanism study suggested that the strong binding affinity with the phospholipids, particularly the cardiolipin, played an important role in the fluoroamphiphiles' mitochondrial targeting. These charge-neutral fluoroamphiphiles might have great potential to be a simple and reliable tool for intracellular drug delivery and mitochondrial targeting.
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Affiliation(s)
- Yin Liu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang Province 330106, China
| | - Jian Zhang
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States
| | - Ying Tu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States
| | - Lin Zhu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States
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Sumida Y, Yoneda M, Seko Y, Takahashi H, Hara N, Fujii H, Itoh Y, Yoneda M, Nakajima A, Okanoue T. Role of vitamin E in the treatment of non-alcoholic steatohepatitis. Free Radic Biol Med 2021; 177:391-403. [PMID: 34715296 DOI: 10.1016/j.freeradbiomed.2021.10.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | | | - Nagisa Hara
- Liver Center, Saga University Hospital, Saga, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Li X, Kong L, Hu W, Zhang C, Pich A, Shi X, Wang X, Xing L. Safe and efficient 2D molybdenum disulfide platform for cooperative imaging-guided photothermal-selective chemotherapy: A preclinical study. J Adv Res 2021; 37:255-266. [PMID: 35499043 PMCID: PMC9039738 DOI: 10.1016/j.jare.2021.08.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 07/21/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
Abstract
Safe and efficient platform of TOS married MoS2 is synthesized by judicious designed for multimode theranostics of ovarian carcinoma. A photothermal conversion efficiency of 65.3% of the platform is higher than that of other materials reported elsewhere. Highly efficient photothermal ablation under safe irradiation and significantly improved selective chemotherapy for tumor. Synergistic therapy, suppressed recurrence, and negligible side effects enable the prominent survival rate of 100% over 91 days for the tumor-bearing mice. A promising candidate for precise nanomedicines in clinical translation. Introduction The striking imbalance between the ever-increasing amount of nanomedicines and low clinical translation of products has become the focus of intense debate. For clinical translation, the critical issue is to select the appropriate agents and combination regimen for targeted diseases, not to prepare increasingly complex nanoplatforms. Objectives A safe and efficient platform, α-tocopheryl succinate (α-TOS) married 2D molybdenum disulfide, was devised by a facile method and applied for cooperative imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Methods A novel platform of PEGylated α-TOS and folic acid (FA) conjugated 2D MoS2 nanoflakes was fabricated for the cooperative multimode computed tomography (CT)/photoacoustic (PA)/thermal imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Results The photothermal efficiency (65.3%) of the platform under safe near-infrared irradiation is much higher than that of other photothermal materials reported elsewhere. Moreover, the covalently linked α-TOS renders platform with selective chemotherapy for cancer cells. Remarkably, with these excellent properties, the platform can be used to completely eliminate the solid tumor by safe photothermal therapy, and then kill the residual cancer cells by selective chemotherapy to prevent tumor recurrence. More significantly, barely side effects occur in the whole treatment process. The excellent efficacy and safety benefits in vivo lead to the prominent survival rate of 100% over 91 days. Conclusion The safe and efficient platform might be a candidate of clinical nanomedicines for multimode theranostics. This study demonstrates an innovative thought in precise nanomedicine regarding the design of next generation of cancer theranostic protocol for potential clinical practice.
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Affiliation(s)
- Xin Li
- Department of Gynecology and Obstetrics, XinHua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai 200092, China
- DWI-Leibniz-Institute for Interactive Materials e.V., 52056 Aachen, Germany
- Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany
| | - Lingdan Kong
- Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China
| | - Wei Hu
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
| | - Changchang Zhang
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
| | - Andrij Pich
- DWI-Leibniz-Institute for Interactive Materials e.V., 52056 Aachen, Germany
- Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany
- Aachen Maastricht Institute for Biobased Materials, Maastricht University, 6167 RD Geleen, the Netherlands
| | - Xiangyang Shi
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal
- Corresponding authors.
| | - Xipeng Wang
- Department of Gynecology and Obstetrics, XinHua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai 200092, China
- Corresponding authors.
| | - Lingxi Xing
- Department of Gynecology and Obstetrics, XinHua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai 200092, China
- Corresponding authors.
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Gok S, Kuzmenko O, Babinskyi A, Severcan F. Vitamin E Derivative with Modified Side Chain Induced Apoptosis by Modulating the Cellular Lipids and Membrane Dynamics in MCF7 Cells. Cell Biochem Biophys 2021; 79:271-287. [PMID: 33442824 DOI: 10.1007/s12013-020-00961-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 12/04/2020] [Indexed: 10/22/2022]
Abstract
The vitamin E derivative with side chain modification (TC6OAc) has been shown to possess anticancer activity in our earlier in vivo studies. It was hypothesized that, as Vitamin E (VE) and VE derivative are fat soluble lipophilic molecules, they exert their function by modulating the lipid metabolism and related pathways. This study aimed to evaluate the cellular impact of this VE derivative (2,5,7,8-Tetramethyl-2-(4'-Methyl-3'-Pentenyl)-6-Acetoxy Chromane-TC6OH), using α-tocopherol as a reference compound throughout the experiments. Their effects on the cellular metabolism, the biophysical properties of cellular lipids and the functional characteristics of cells were monitored in human estrogen receptor (ER) positive breast cancer cells. It has been documented that TC6OH treatment induces tumor cell apoptosis by dissipating the mitochondrial membrane potential, modulating the lipid, transportation and degradation as well as downregulating certain anti-apoptotic and growth factor related proteins. Due to resistance of ER positive cells to the established therapies, the findings of this study are of translational value.
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Affiliation(s)
- Seher Gok
- The Scientific and Technological Research Council of Turkey, Ankara, Turkey
| | - Oleksandr Kuzmenko
- Department of Vitamins and Coenzymes Biochemistry, Palladin Institute of Biochemistry, Kiev, Ukraine
| | - Andrii Babinskyi
- Department of Vitamins and Coenzymes Biochemistry, Palladin Institute of Biochemistry, Kiev, Ukraine
| | - Feride Severcan
- Faculty of Medicine, Department of Biophysics, Altinbas University, Istanbul, Turkey.
- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
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15
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Hafez SMNA, Elbassuoni E, Abdelzaher WY, Welson NN, Batiha GES, Alzahrani KJ, Abdelbaky FAF. Efficacy of vitamin E in protection against methotrexate induced placental injury in albino rats. Biomed Pharmacother 2021; 139:111637. [PMID: 33965732 DOI: 10.1016/j.biopha.2021.111637] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/13/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022] Open
Abstract
Methotrexate (MXT) is a chemotherapeutic drug that has been used in a wide range of clinical practices. Unfortunately, the administration of MXT during pregnancy may induce abortion, fetal deformities, and intrauterine growth retardation. Vitamin E is an antioxidant agent that can ameliorate free radical damage. The current work aimed to shed more light on the possible protective effect of vitamin E against MXT induced placental toxicity and to determine the possible mechanisms; biochemically, histologically, and immunohistochemically. Four groups were used: control pregnant, Vitamin E (VIT E) pregnant, Methotrexate (MXT) pregnant, and Vitamin E Methotrexate (VIT E-MXT) pregnant. The placental tissues were processed for light, immunohistochemical, and electron microscopic study. Other samples were obtained for biochemical study; the placental oxidant/antioxidant status was evaluated. The results showed that MXT caused various placental morphological changes in the form of distorted chorionic projection with an accumulation of hemosiderin granules in the trophoblastic cells. Maternal blood vessels showed a homogenous acidophilic material Edema of the extra-embryonic fetal membranes was noticed. A significant decreased in placental weight as well as increase in the oxidative and inflammatory markers were detected. Increased COX2 and decreased eNOS expressions were observed in the MXT group if compared to the control group. VIT E significantly restored the normal histological and immunohistochemical appearance, placental weight, and oxidant/antioxidant balance. It could be concluded the biochemical, morphological, and morphometric findings suggested that vitamin E coadministration is promising in attenuating the placental toxic effect of methotrexate. In this study, VIT E decreased the inflammatory and oxidative stress effect of methotrexate on the placental tissue by enhancing the level of eNOS.
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Affiliation(s)
| | - Eman Elbassuoni
- Physiology Department, Minia University, Faculty of Medicine, Minia, Egypt.
| | | | - Nermeen N Welson
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Egypt.
| | - Khalid J Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
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16
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Debele TA, Wu HC, Wu SR, Shan YS, Su WP. Combination Delivery of Alpha-Tocopheryl Succinate and Curcumin Using a GSH-Sensitive Micelle (PAH-SS-PLGA) to Treat Pancreatic Cancer. Pharmaceutics 2020; 12:pharmaceutics12080778. [PMID: 32824299 PMCID: PMC7464675 DOI: 10.3390/pharmaceutics12080778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 01/13/2023] Open
Abstract
Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (1H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments.
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Affiliation(s)
- Tilahun Ayane Debele
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng Li Road, Tainan 704, Taiwan; (T.A.D.); (Y.-S.S.)
| | - Hung-Chang Wu
- Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan;
| | - Shang-Rung Wu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Department of Dentistry & Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng Li Road, Tainan 704, Taiwan; (T.A.D.); (Y.-S.S.)
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Wen-Pin Su
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng Li Road, Tainan 704, Taiwan; (T.A.D.); (Y.-S.S.)
- Departments of Oncology and Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Correspondence: ; Tel.: +886-6-2353535 (ext. 4252)
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Boratto FA, Franco MS, Barros ALB, Cassali GD, Malachias A, Ferreira LAM, Leite EA. Alpha-tocopheryl succinate improves encapsulation, pH-sensitivity, antitumor activity and reduces toxicity of doxorubicin-loaded liposomes. Eur J Pharm Sci 2019; 144:105205. [PMID: 31874285 DOI: 10.1016/j.ejps.2019.105205] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/27/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023]
Abstract
Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed to attenuate the DOX toxicity, but the technological enhancement of the liposomal formulation as well as the addition of another agent with antitumor properties, like alpha-tocopheryl succinate (TS), a semi-synthetic analog of vitamin E, could certainly bring benefits. Thus, in this study, it was proposed the development of liposomes composed of DOX and TS (pHSL-TS-DOX). A new DOX encapsulation method, without using the classic ammonium sulfate gradient with high encapsulation percentage was developed. Analysis of Small Angle X-ray Scattering (SAXS) and release study proved the pH-sensitivity of the developed formulation. It was observed stabilization of tumor growth using pHSL-TS-DOX when compared to free DOX. The toxicity tests showed the safety of this formulation since it allowed body weight initial recovery after the treatment and harmless to heart and liver, main target organs of DOX toxicity. The developed formulation also avoided the occurrence of myelosuppression, a typical adverse effect of DOX. Therefore, pHSL-TS-DOX is a promising alternative for the treatment of breast cancer since it has adequate antitumor activity and a safe toxicity profile.
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Affiliation(s)
- F A Boratto
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - M S Franco
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - A L B Barros
- Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - G D Cassali
- Department of Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - A Malachias
- Department of Physics, Institute of Exact Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - L A M Ferreira
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - E A Leite
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
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Javadpour P, Dargahi L, Ahmadiani A, Ghasemi R. To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling. Cell Mol Life Sci 2019; 76:2277-2297. [PMID: 30874837 PMCID: PMC11105459 DOI: 10.1007/s00018-019-03063-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 02/16/2019] [Accepted: 03/07/2019] [Indexed: 12/26/2022]
Abstract
Accumulating evidence has reached the consensus that the balance of phosphorylation state of signaling molecules is a pivotal point in the regulation of cell signaling. Therefore, characterizing elements (kinases-phosphatases) in the phosphorylation balance are at great importance. However, the role of phosphatase enzymes is less investigated than kinase enzymes. PP2A is a member of serine/threonine protein phosphatase that its imbalance has been reported in neurodegenerative diseases. Therefore, we reviewed the superfamily of phosphatases and more specifically PP2A, its regulation, and physiological functions participate in CNS. Thereafter, we discussed the latest findings about PP2A dysregulation in Alzheimer and Parkinson diseases and possible interplay between this phosphatase and insulin signaling pathways. Finally, activating/inhibitory modulators for PP2A activity as well as experimental methods for PP2A study have been reviewed.
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Affiliation(s)
- Pegah Javadpour
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Ghasemi
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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19
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Lee SY, Cho HJ. Mitochondria Targeting and Destabilizing Hyaluronic Acid Derivative-Based Nanoparticles for the Delivery of Lapatinib to Triple-Negative Breast Cancer. Biomacromolecules 2018; 20:835-845. [DOI: 10.1021/acs.biomac.8b01449] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Song Yi Lee
- College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Hyun-Jong Cho
- College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
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Du X, Yin S, Zhou F, Du X, Xu J, Gu X, Wang G, Li J. Reduction-sensitive mixed micelles for selective intracellular drug delivery to tumor cells and reversal of multidrug resistance. Int J Pharm 2018; 550:1-13. [DOI: 10.1016/j.ijpharm.2018.08.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/31/2018] [Accepted: 08/12/2018] [Indexed: 12/17/2022]
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21
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Hepatocellular carcinomas are promoted by tocopheryl acetate but eliminated by tocopheryl succinate. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2018. [DOI: 10.1016/j.jnim.2018.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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22
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Bhori M, Singh K, Marar T, Chilakapati MK. Exploring the effect of vitamin E in cancer chemotherapy-A biochemical and biophysical insight. JOURNAL OF BIOPHOTONICS 2018; 11:e201800104. [PMID: 29770585 DOI: 10.1002/jbio.201800104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/15/2018] [Indexed: 06/08/2023]
Abstract
Many oncologists contend that patient undergoing chemotherapy must avoid antioxidant supplementation as it may interfere with the activity of the drug. In the present investigation, we have explored the influence of vitamin E, a well-known antioxidant on Camptothecin (CPT), a potent anti-cancer drug induced cell apoptosis and death of cervical cancer cells. HeLa cells were treated with different concentrations of CPT in presence and absence of 100 μm vitamin E. Treated cells were subjected to cytotoxicity studies, catalase assay, DNA fragmentation assay, clonogenic assay and flow cytometry based apoptosis detection. Also, Raman spectroscopy a label free technique which provides global information, in conjunction with multivariate tools like PCA, PCLDA and FDA, was investigated to explore vitamin E supplementation induced alterations. Our data based on biochemical and biophysical experimental analysis reveals that CPT causes DNA damage along with protein and lipid alteration culminating in cell death. Importantly, Raman spectroscopic analysis could uniquely differentiate the cluster of control and vitamin E control from CPT and CPT + Vit E treated cells. We conclusively prove that presence of vitamin E at 100 μM concentration shows promising antioxidant activity and displays no modulatory role on CPT induced effect, thereby causing no possible hindrance with the efficacy of the drug. Vitamin E may prove beneficial to alleviate chemotherapy associated side effects in patients during clinical settings which may open the doors further for subsequent exploration in in vivo preclinical studies.
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Affiliation(s)
- Mustansir Bhori
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed to be University, Navi Mumbai, India
| | - Kanchanlata Singh
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed to be University, Navi Mumbai, India
| | - Thankamani Marar
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed to be University, Navi Mumbai, India
| | - Murali Krishna Chilakapati
- Chilakapati Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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23
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Battogtokh G, Cho YY, Lee JY, Lee HS, Kang HC. Mitochondrial-Targeting Anticancer Agent Conjugates and Nanocarrier Systems for Cancer Treatment. Front Pharmacol 2018; 9:922. [PMID: 30174604 PMCID: PMC6107715 DOI: 10.3389/fphar.2018.00922] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/26/2018] [Indexed: 12/30/2022] Open
Abstract
The mitochondrion is an important intracellular organelle for drug targeting due to its key roles and functions in cellular proliferation and death. In the last few decades, several studies have revealed mitochondrial functions, attracting the focus of many researchers to work in this field over nuclear targeting. Mitochondrial targeting was initiated in 1995 with a triphenylphosphonium-thiobutyl conjugate as an antioxidant agent. The major driving force for mitochondrial targeting in cancer cells is the higher mitochondrial membrane potential compared with that of the cytosol, which allows some molecules to selectively target mitochondria. In this review, we discuss mitochondria-targeting ligand-conjugated anticancer agents and their in vitro and in vivo behaviors. In addition, we describe a mitochondria-targeting nanocarrier system for anticancer drug delivery. As previously reported, several agents have been known to have mitochondrial targeting potential; however, they are not sufficient for direct application for cancer therapy. Thus, many studies have focused on direct conjugation of targeting ligands to therapeutic agents to improve their efficacy. There are many variables for optimal mitochondria-targeted agent development, such as choosing a correct targeting ligand and linker. However, using the nanocarrier system could solve some issues related to solubility and selectivity. Thus, this review focuses on mitochondria-targeting drug conjugates and mitochondria-targeted nanocarrier systems for anticancer agent delivery.
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Affiliation(s)
| | | | | | | | - Han Chang Kang
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea
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Kume A, Kasai S, Furuya H, Suzuki H. α-Tocopheryl succinate-suppressed development of cerebral malaria in mice. Parasitol Res 2018; 117:3177-3182. [PMID: 30030625 DOI: 10.1007/s00436-018-6016-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 07/12/2018] [Indexed: 12/13/2022]
Abstract
α-Tocopheryl succinate (α-TOS), a derivative of vitamin E, is synthesized by esterification of α-tocopherol. It has been reported that α-TOS inhibits the mitochondrial complex II resulting in generation of reactive oxygen species, which triggers selective apoptosis in a large number of cancer cells, while it appears largely non-toxic towards normal cells. Plasmodium parasites are well known to have high sensitivity to oxidative stress. Thus, α-TOS is suspected to impact Plasmodium parasites by oxidative stress. In this study, to ascertain whether α-TOS is an appropriate candidate for an anti-malarial drug, C57BL/6J mice were infected with P. yoelii 17XL and P. berghei ANKA, a lethal strain of rodent malaria and experimental cerebral malaria (ECM), and treated with several concentrations of α-TOS by intraperitoneal administration on 1, 3, 5, and 7 days post infection (dpi). In addition, the permeability of the blood brain barrier (BBB) was examined by Evans blue staining in ECM on 7 dpi. As a result of α-TOS treatment, parasitemia was decreased and survival rate was significantly increased in mice infected with both parasites. Furthermore, the intensity of Evans blue staining on brains taken from α-TOS-treated mice was weaker than that of untreated mice. This means that α-TOS might inhibit the breakdown of BBB and progress of cerebral malaria. These findings indicate that vitamin E derivatives like α-TOS might be a potential candidate for treatment drugs against malaria.
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Affiliation(s)
- Aiko Kume
- Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan
| | - Shunji Kasai
- Eisai Co., Ltd., 13-1 Nishigoken-cho, Shinjuku-ku, Tokyo, 162-0812, Japan
| | - Hana Furuya
- Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan
| | - Hiroshi Suzuki
- Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.
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25
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Weidenbusch B, Richter GHS, Kesper MS, Guggemoos M, Gall K, Prexler C, Kazantsev I, Sipol A, Lindner L, Nathrath M, Witt O, Specht K, Beitinger F, Knebel C, Hosie S, von Eisenhardt-Rothe R, Weichert W, Luettichau ITV, Burdach S. Transcriptome based individualized therapy of refractory pediatric sarcomas: feasibility, tolerability and efficacy. Oncotarget 2018; 9:20747-20760. [PMID: 29755686 PMCID: PMC5945512 DOI: 10.18632/oncotarget.25087] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 03/05/2018] [Indexed: 01/12/2023] Open
Abstract
Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient’s tumor and guide the choice of therapy. Twenty patients with refractory pediatric sarcomas (age 8-35 years) were assessed with array profiling: ten had Ewing sarcoma, five osteosarcoma, and five soft tissue sarcoma. Overexpressed genes and deregulated pathways were identified as actionable targets and an individualized combination of targeted therapies was recommended. Disease status, survival, adverse events (AEs), and quality of life (QOL) were assessed in patients receiving targeted therapy (TT) and compared to patients without targeted therapy (non TT). Actionable targets were identified in all analyzed biopsies. Targeted therapy was administered in nine patients, while eleven received no targeted therapy. No significant difference in risk factors between these two groups was detected. Overall survival (OS) and progression free survival (PFS) were significantly higher in the TT group (OS: P=0.0014, PFS: P=0.0011). Median OS was 8.83 versus 4.93 months and median PFS was 6.17 versus 1.6 months in TT versus non TT group, respectively. QOL did not differ at baseline as well as at four week intervals between the two groups. TT patients had less grade 1 AEs (P=0.009). The frequency of grade 2-4 AEs did not differ. Overall, expression based targeted therapy is a feasible and likely beneficial approach in patients with refractory pediatric sarcomas that warrants further study.
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Affiliation(s)
- Bushra Weidenbusch
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany
| | - Günther H S Richter
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
| | - Marie Sophie Kesper
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
| | - Monika Guggemoos
- Department of Pharmacology, Städtisches Klinikum München GmbH, Munich, Germany
| | - Katja Gall
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany
| | - Carolin Prexler
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
| | - Ilya Kazantsev
- RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Alexandra Sipol
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany
| | - Lars Lindner
- Department of Hematology/Oncology, Munich University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Michaela Nathrath
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,Department of Pediatric Hematology and Oncology, Klinikum Kassel, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
| | - Olaf Witt
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Katja Specht
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Frigga Beitinger
- Department of Pathology, Städtisches Klinikum München GmbH, Munich, Germany
| | - Carolin Knebel
- Department of Orthopedic Surgery, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany
| | - Stuart Hosie
- Department of Pediatric Surgery, Städtisches Klinikum München GmbH, Munich, Germany
| | - Rüdiger von Eisenhardt-Rothe
- Department of Orthopedic Surgery, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany
| | - Wilko Weichert
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Irene Teichert-von Luettichau
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
| | - Stefan Burdach
- Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Klinikum rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.,CCC München - Comprehensive Cancer Center; and DKTK German Cancer Consortium Munich, Munich, Germany
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26
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Song Y, Cai H, Yin T, Huo M, Ma P, Zhou J, Lai W. Paclitaxel-loaded redox-sensitive nanoparticles based on hyaluronic acid-vitamin E succinate conjugates for improved lung cancer treatment. Int J Nanomedicine 2018; 13:1585-1600. [PMID: 29588586 PMCID: PMC5858821 DOI: 10.2147/ijn.s155383] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment. Methods The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model. Results This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL−1. Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol®, PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX. Conclusion The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy.
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Affiliation(s)
- Yu Song
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.,College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China
| | - Han Cai
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Tingjie Yin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Meirong Huo
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Ping Ma
- Formulation Development, Tolmar Inc, Fort Collins, CO, USA
| | - Jianping Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Wenfang Lai
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China
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27
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Singh RK, Kumar S, Gautam PK, Tomar MS, Verma PK, Singh SP, Kumar S, Acharya A. Protein kinase C-α and the regulation of diverse cell responses. Biomol Concepts 2018; 8:143-153. [PMID: 28841566 DOI: 10.1515/bmc-2017-0005] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 07/18/2017] [Indexed: 11/15/2022] Open
Abstract
Protein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-α is a member of classical PKC with ubiquitous expression and different cellular localization. This unique PKC isoform is activated by various signals which evoke lipid hydrolysis, after activation it interacts with various adapter proteins and is localized to specific cellular compartments where it is devised to work. The universal expression and activation by various stimuli make it a perfect player in uncountable cellular functions including differentiation, proliferation, apoptosis, cellular transformation, motility, adhesion and so on. However, these functions are not intrinsic properties of PKC-α, but depend on cell types and conditions. The activities of PKC-α are managed by the various pharmacological activators/inhibitors and antisense oligonucleotides. The aim of this review is to elaborate the structural feature, and provide an insight into the mechanism of PKC-α activation and regulation of its key biological functions in different cellular compartments to develop an effective pharmacological approach to regulate the PKC-α signal array.
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28
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Pan Y, Wang N, Xia P, Wang E, Guo Q, Ye Z. Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway. Exp Neurol 2017; 300:149-166. [PMID: 29129468 DOI: 10.1016/j.expneurol.2017.10.030] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 10/20/2017] [Accepted: 10/30/2017] [Indexed: 01/28/2023]
Abstract
Although the neuroprotective effects of Rac1 inhibition have been reported in various cerebral ischemic models, the molecular mechanisms of action have not yet been fully elucidated. In this study, we investigated whether the inhibition of Rac1 provided neuroprotection in a diabetic rat model of focal cerebral ischemia and hyperglycemia-exposed PC-12 cells. Intracerebroventricular administration of lentivirus expressing the Rac1 small hairpin RNA (shRNA) and specific Rac1 inhibitor NSC23766 not only decreased the infarct volumes and improved neurologic deficits with a correlated significant activation of mitochondrial DNA specific proteins, such as OGG1 and POLG, but also elevated Bcl-2 S70 phosphorylation in mitochondria. Furthermore, the levels of p-PI3K, p-Akt and p-mTOR increased, while 8-OHdG, ROS production and Bcl-2/Rac1 complex formation in mitochondria reduced in both Rac1-shRNA- and NSC23766-treated rats. Moreover, to confirm our in vivo observations, inhibition of Rac1 activity by NSC23766 suppressed the interactions between Bcl-2 and Rac1 in the mitochondria of PC-12 cells cultured in high glucose conditions and protected PC-12 cells from high glucose-induced neurotoxicity. More importantly, these beneficial effects of Rac1 inhibition were abolished by PI3K inhibitor LY294002. In contrast to NSC23766 treatment, LY294002 had little effect on the decrement of p-PTEN level. Taken together, these findings revealed novel neuroprotective roles of Rac1 inhibition against cerebral ischemic reperfusion injury in vivo and high glucose-induced neurotoxicity in PC-12 cells in vitro, by reducing Bcl-2/Rac1 complex formation in mitochondria through the activation of PI3K/Akt/mTOR survival pathway.
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Affiliation(s)
- Yundan Pan
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China
| | - Na Wang
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China
| | - Pingping Xia
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China
| | - E Wang
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China
| | - Qulian Guo
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China
| | - Zhi Ye
- Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China.
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29
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Therapeutic targeting of PP2A. Int J Biochem Cell Biol 2017; 96:182-193. [PMID: 29107183 DOI: 10.1016/j.biocel.2017.10.008] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/13/2017] [Accepted: 10/16/2017] [Indexed: 12/19/2022]
Abstract
Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies.
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30
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Debele TA, Lee KY, Hsu NY, Chiang YT, Yu LY, Shen YA, Lo CL. A pH sensitive polymeric micelle for co-delivery of doxorubicin and α-TOS for colon cancer therapy. J Mater Chem B 2017; 5:5870-5880. [PMID: 32264220 DOI: 10.1039/c7tb01031a] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Combination therapy through simultaneous delivery of two or more therapeutic agents using nanocarriers has emerged as an advanced tactic for cancer treatment. To ensure that two therapeutic agents can be co-delivered and rapidly release their cargo in tumor cells, a biocompatible pH-sensitive copolymer, methoxy poly(ethylene glycol)-b-poly(hydroxypropyl methacrylamide-g-α-tocopheryl succinate-g-histidine) (abbreviated as PTH), was designed and synthesized. The PTH copolymers spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and are used for co-delivery of therapeutic agents, doxorubicin (Dox) and α-TOS. During micellization, π-π stacking occurred between Dox/α-TOS and imidazole rings of PTH copolymers inducing a regular and tight arrangement of copolymers and drugs to form rod-like micelles, thus efficiently increasing the drug loading and encapsulation efficiency. The micelles enabled the rapid release of both Dox and α-TOS when the pH decreased from 7.4 to 4.5. The protein adsorption assay revealed that low amounts of IgG and BSA were adsorbed on the micelles. In vivo biodistribution demonstrated that the micelles could largely accumulate in the tumor tissues. Furthermore, drug-loaded micelles treated with HCT116 cancer cells exhibited higher cytotoxicity than normal cells, which confirmed that α-TOS exhibited a synergy effect with Dox towards cancer cells, while no recognizable side effects were observed during the treatment from organ function tests.
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Affiliation(s)
- Tilahun Ayane Debele
- Department of Biomedical Engineering, National Yang Ming University, Taipei 112, Taiwan.
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31
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Tian Q, Shi J, Zhao X, Di D, Deng Y, Song Y. The antitumor efficacy of docetaxel is enhanced by encapsulation in novel amphiphilic polymer cholesterol-coupled tocopheryl polyethylene glycol 1000 succinate micelles. Drug Deliv Transl Res 2017; 7:642-653. [PMID: 28695431 DOI: 10.1007/s13346-017-0403-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Bezawork-Geleta A, Rohlena J, Dong L, Pacak K, Neuzil J. Mitochondrial Complex II: At the Crossroads. Trends Biochem Sci 2017; 42:312-325. [PMID: 28185716 DOI: 10.1016/j.tibs.2017.01.003] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 01/06/2017] [Accepted: 01/10/2017] [Indexed: 02/06/2023]
Abstract
Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited.
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Affiliation(s)
| | - Jakub Rohlena
- Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia
| | - Lanfeng Dong
- School of Medical Science, Griffith University, Southport, Australia
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Jiri Neuzil
- School of Medical Science, Griffith University, Southport, Australia; Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia.
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33
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Savitskaya MA, Onischenko GE. α-Tocopheryl Succinate Affects Malignant Cell Viability, Proliferation, and Differentiation. BIOCHEMISTRY (MOSCOW) 2017; 81:806-18. [PMID: 27677550 DOI: 10.1134/s0006297916080034] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The widespread occurrence of malignant tumors motivates great attention to finding and investigating effective new antitumor preparations. Such preparations include compounds of the vitamin E family. Among them, α-tocopheryl succinate (vitamin E succinate (VES)) has the most pronounced antitumor properties. In this review, various targets and mechanisms of the antitumor effect of vitamin E succinate are characterized. It has been shown that VES has multiple intracellular targets and effects, and as a result VES is able to induce apoptosis in tumor cells, inhibit their proliferation, induce differentiation, prevent metastasizing, and inhibit angiogenesis. However, VES has minimal effects on normal cells and tissues. Due to the variety of targets and selectivity of action, VES is a promising agent against malignant neoplasms. More detailed studies in this area can contribute to development of effective and safe chemotherapeutic preparations.
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Affiliation(s)
- M A Savitskaya
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119991, Russia.
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Rohlenova K, Sachaphibulkij K, Stursa J, Bezawork-Geleta A, Blecha J, Endaya B, Werner L, Cerny J, Zobalova R, Goodwin J, Spacek T, Alizadeh Pesdar E, Yan B, Nguyen MN, Vondrusova M, Sobol M, Jezek P, Hozak P, Truksa J, Rohlena J, Dong LF, Neuzil J. Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2 high Breast Cancer. Antioxid Redox Signal 2017; 26:84-103. [PMID: 27392540 PMCID: PMC5206771 DOI: 10.1089/ars.2016.6677] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AIMS Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. RESULTS We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. INNOVATION Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.
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Affiliation(s)
- Katerina Rohlenova
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | | | - Jan Stursa
- 2 School of Medical Science, Griffith University , Southport, Australia .,3 Prague Institute of Chemical Technology , Prague, Czech Republic .,4 Biomedical Research Center, University Hospital , Hradec Kralove, Czech Republic
| | | | - Jan Blecha
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | - Berwini Endaya
- 2 School of Medical Science, Griffith University , Southport, Australia
| | - Lukas Werner
- 4 Biomedical Research Center, University Hospital , Hradec Kralove, Czech Republic
| | - Jiri Cerny
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | - Renata Zobalova
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .,2 School of Medical Science, Griffith University , Southport, Australia
| | - Jacob Goodwin
- 2 School of Medical Science, Griffith University , Southport, Australia
| | - Tomas Spacek
- 5 Institute of Physiology , Prague, Czech Republic
| | | | - Bing Yan
- 2 School of Medical Science, Griffith University , Southport, Australia
| | - Maria Nga Nguyen
- 2 School of Medical Science, Griffith University , Southport, Australia
| | - Magdalena Vondrusova
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | - Margaryta Sobol
- 6 Institute of Molecular Genetics , Czech Academy of Sciences, Prague, Czech Republic
| | - Petr Jezek
- 5 Institute of Physiology , Prague, Czech Republic
| | - Pavel Hozak
- 6 Institute of Molecular Genetics , Czech Academy of Sciences, Prague, Czech Republic
| | - Jaroslav Truksa
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | - Jakub Rohlena
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
| | - Lan-Feng Dong
- 2 School of Medical Science, Griffith University , Southport, Australia
| | - Jiri Neuzil
- 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .,2 School of Medical Science, Griffith University , Southport, Australia
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Qu Q, Ma X, Zhao Y. Anticancer Effect of α-Tocopheryl Succinate Delivered by Mitochondria-Targeted Mesoporous Silica Nanoparticles. ACS APPLIED MATERIALS & INTERFACES 2016; 8:34261-34269. [PMID: 27998109 DOI: 10.1021/acsami.6b13974] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Mitochondria targeted mesoporous silica nanoparticles (MSNPs) having an average diameter of 68 nm were fabricated and then loaded with hydrophobic anticancer agent α-tocopheryl succinate (α-TOS). The property of targeting mitochondria was achieved by the surface functionalization of triphenylphosphonium (TPP) on MSNPs, since TPP is an effective mitochondria-targeting ligand. Intracellular uptake and mitochondria targeting of fabricated MSNPs were evaluated in HeLa and HepG2 cancerous cell lines as well as HEK293 normal cell line. In addition, various biological assays were conducted with the aim to investigate the effectiveness of α-TOS delivered by the functional MSNPs, including studies of cytotoxicity, mitochondria membrane potential, intracellular adenosine triphosphate (ATP) production, and apoptosis. On the basis of these experiments, high anticancer efficiency of α-TOS delivered by mitochondria targeted MSNPs was demonstrated, indicating a promising application potential of MSNP-based platform in mitochondria targeted delivery of anticancer agents.
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Affiliation(s)
- Qiuyu Qu
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore
| | - Xing Ma
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore
| | - Yanli Zhao
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore
- School of Materials Science and Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
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Ambrogini P, Betti M, Galati C, Di Palma M, Lattanzi D, Savelli D, Galli F, Cuppini R, Minelli A. α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions. Int J Mol Sci 2016; 17:E2107. [PMID: 27983697 PMCID: PMC5187907 DOI: 10.3390/ijms17122107] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/01/2016] [Accepted: 12/09/2016] [Indexed: 12/25/2022] Open
Abstract
Neuroplasticity is an "umbrella term" referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular α-tocopherol (α-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/α-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/α-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity.
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Affiliation(s)
- Patrizia Ambrogini
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Michele Betti
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Claudia Galati
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Michael Di Palma
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Davide Lattanzi
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - David Savelli
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
| | - Riccardo Cuppini
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
| | - Andrea Minelli
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy.
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37
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Yu Y, Hou L, Song H, Xu P, Sun Y, Wu K. Akt/AMPK/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells. Mol Cell Biochem 2016; 424:173-183. [PMID: 27796683 DOI: 10.1007/s11010-016-2853-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 10/22/2016] [Indexed: 12/18/2022]
Abstract
Vitamin E succinate (VES), a derivative of vitamin E, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing apoptotic cell death. The effects of VES on autophagy, an intricate programmed process which helps cells survive in some stressed situations by degrading some cytoplasmic material, are unclear. When human gastric cancer cells SCG-7901 were exposed to VES, both the level of microtubule-associated protein 1 light chain 3 and the yeast ATG6 homolog Beclin-1 increased, and related autophagy genes were activated, thereby suggesting that autophagy was induced by VES. We also observed that VES-induced autophagy was accompanied by the activation of AMP-activated protein kinases (AMPK). VES-induced autophagy decreased when AMPK was inhibited by using small interfering RNA (siRNA), thereby suggesting that VES-induced autophagy is mediated by AMPK. Moreover, further studies revealed that the decreased activity of mammalian target of rapamycin (mTOR) and its downstream targets P70S6K and 4EBP-1 were involved in VES-activated autophagy associated with AMPK activation. The experiments also showed that the activity of protein kinases B (Akt)-mTOR axis was inhibited by VES. VES-induced AMPK activation could be attenuated by Akt activation. Overall, our studies demonstrated that AMPK was involved in the VES-induced autophagy. Crosstalk exists between AMPK and the Akt/mTOR axis. The results elucidated the mechanism of VES-induced autophagy in human gastric cancer cells.
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Affiliation(s)
- Yang Yu
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China
| | - Liying Hou
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Huacui Song
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China
| | - Peixiang Xu
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China
| | - Yue Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China
| | - Kun Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China.
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Bacci C, Vanzo V, Frigo AC, Stellini E, Sbricoli L, Valente M. Topical tocopherol for treatment of reticular oral lichen planus: a randomized, double-blind, crossover study. Oral Dis 2016; 23:62-68. [DOI: 10.1111/odi.12573] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/19/2016] [Accepted: 07/27/2016] [Indexed: 01/16/2023]
Affiliation(s)
- C Bacci
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
| | - V Vanzo
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
| | - AC Frigo
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
| | - E Stellini
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
| | - L Sbricoli
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
| | - M Valente
- Department of Neurosciences; Section of Clinical Dentistry; University of Padova; Padova Italy
- Department of Cardiac; Thoracic and Vascular Sciences; University of Padova; Padova Italy
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Hou L, Zhang H, Xu P, Zhang L, Zhang X, Sun Y, Huang X, Wu K. Effect of vitamin E succinate on the expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor in gastric cancer cells and CD4(+) T cells. MOLECULAR BIOSYSTEMS 2016; 11:3119-28. [PMID: 26378383 DOI: 10.1039/c5mb00350d] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Gastric malignancy, which shows poor prognosis, is one of the most frequent causes of cancer-associated deaths. Vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis in a concentration- and time-dependent manner. We explored the effect of VES on the expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor in gastric cancer cells and CD4(+) T cells. On one hand, VES dose-dependently regulated the expression of the TRAIL receptor in gastric cancer cells. Moreover, the activation of the TRAIL receptor, death receptor 4 (DR4), and death receptor 5 (DR5) in gastric cancer cells increased for up to 12 h. On the other hand, the expression of TRAIL protein in human CD4(+) T cells was obviously upregulated in the presence of VES. On the basis of these findings, we combined VES and human CD4(+) T cells to induce apoptosis of MKN28 human gastric cancer cells. The results showed that VES induced higher gastric cancer cell apoptosis when combined with human CD4(+) T cells than when applied alone. We conclude that VES can induce the expression of TRAIL receptor in gastric cancer cells, as well as the expression of TRAIL in CD4(+) T cells. Overall, our results provide a theoretical basis for future immunotherapy studies.
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Affiliation(s)
- Liying Hou
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 150081 Harbin, China.
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40
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Scaringi L, Cornacchione P, Ayroldi E, Corazzi L, Capodicasa E, Rossi R, Marconi P. Omeprazole Induces Apoptosis in Jurkat Cells. Int J Immunopathol Pharmacol 2016; 17:331-42. [PMID: 15461867 DOI: 10.1177/039463200401700313] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
We report for the first time a potent apoptotic effect of omeprazole (OM). Apoptosis was induced in Jurkat cells in a time and concentration-dependent mode. Caspase 3 and PARP were rapidly cleaved in response to OM, but apoptosis was only partially inhibited by the caspase 3 inhibitor DEVD-CHO. OM also induced an early lysosomal destabilization which increased progressively and was correlated with a parallel increase in apoptotic cells. The cysteine protease inhibitor E64d gave strong protection against apoptosis thus proving the involvement of lysosomal enzymes in OM-induced apoptosis whereas, it did not impede the caspase 3 cleavage. Instead ZVAD-fmk, a general caspase inhibitor, also able to inhibit cathepsin activity, protected cells completely from OM-induced apoptosis. It therefore seems that both caspases and cysteine cathepsins are involved in the execution stage of OM-induced apoptosis.
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Affiliation(s)
- L Scaringi
- Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, General Hospital, University of Perugia, Perugia, Italy.
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41
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Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs. Eur J Pharm Sci 2016; 88:59-69. [DOI: 10.1016/j.ejps.2016.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/05/2016] [Accepted: 04/05/2016] [Indexed: 12/18/2022]
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Cheng Y, Kerppola RE, Kerppola TK. ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo. Endocr Relat Cancer 2016; 23:1-19. [PMID: 26843528 PMCID: PMC4887102 DOI: 10.1530/erc-15-0527] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/02/2016] [Indexed: 12/26/2022]
Abstract
Adrenocortical carcinoma (ACC) generally has poor prognosis. Existing treatments provide limited benefit for most patients with locally advanced or metastatic tumors. We investigated the mechanisms for the cytotoxicity, xenograft suppression, and adrenalytic activity of ATR-101 (PD132301-02), a prospective agent for ACC treatment. Oral administration of ATR-101 inhibited the establishment and impeded the growth of ACC-derived H295R cell xenografts in mice. ATR-101 induced H295R cell apoptosis in culture and in xenografts. ATR-101 caused mitochondrial hyperpolarization, reactive oxygen release, and ATP depletion within hours after exposure, followed by cytochrome c release, caspase-3/7 activation, and membrane permeabilization. The increase in mitochondrial membrane potential occurred concurrently with the decrease in cellular ATP levels. When combined with ATR-101, lipophilic free radical scavengers suppressed the reactive oxygen release, and glycolytic precursors prevented the ATP depletion, abrogating ATR-101 cytotoxicity. ATR-101 directly inhibited F1F0-ATPase activity and suppressed ATP synthesis in mitochondrial fractions. ATR-101 administration to guinea pigs caused oxidized lipofuscin accumulation in the zona fasciculate layer of the adrenal cortex, implicating reactive oxygen release in the adrenalytic effect of ATR-101. These results support the development of ATR-101 and other adrenalytic compounds for the treatment of ACC.
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Affiliation(s)
- Yunhui Cheng
- Department of Biological ChemistryUniversity of Michigan, Ann Arbor, MI, USA
| | | | - Tom Klaus Kerppola
- Department of Biological ChemistryUniversity of Michigan, Ann Arbor, MI, USA
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The Combination of α-Tocopheryl Succinate and Sodium Selenite on Breast Cancer: A Merit or a Demerit? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:4741694. [PMID: 27127548 PMCID: PMC4834195 DOI: 10.1155/2016/4741694] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 02/05/2016] [Accepted: 02/07/2016] [Indexed: 01/11/2023]
Abstract
α-Tocopheryl succinate (α-TOS), a mitochondria-targeting agent, induces apoptosis in malignant cells in vitro and in vivo. Selenite is a nutritional supplement that has been shown to stimulate apoptosis in cancer cells. This study was designed to investigate the cytotoxic effect of combined treatment of α-TOS and sodium selenite (SSe) in vitro and in vivo and to explore their effect on apoptosis and autophagy in breast cancer. The type of interaction between α-TOS and SSe was evaluated and levels of oxidative stress and apoptotic and autophagic markers were determined. SSe alone showed varying degrees of cytotoxicity on all the tested cell lines. Its combination with α-TOS was antagonistic in vitro in MCF7 and in vivo in mice bearing Ehrlich tumor compared to α-TOS-treated one. Combination of TOS with 2 μM of SSe increased the level of glutathione without changes in antiapoptotic markers Bcl-2 and Mcl-1 at 16 and 48 hrs. SSe decreased caspase 3 activity and protein level of caspases 7 and 9, while it increased autophagic markers beclin-1 and LC3B protein levels of MCF7 cells treated with α-TOS. In conclusion, SSe antagonizes α-TOS-induced apoptosis via inhibition of oxidative stress and promoting prosurvival machinery of autophagy.
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Sangodkar J, Farrington C, McClinch K, Galsky MD, Kastrinsky DB, Narla G. All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J 2016; 283:1004-24. [PMID: 26507691 PMCID: PMC4803620 DOI: 10.1111/febs.13573] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/29/2015] [Accepted: 10/21/2015] [Indexed: 12/22/2022]
Abstract
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is genetically altered or functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. In this review we discuss recent literature on PP2A: the elucidation of its structure and the functions of its subunits, and the identification of molecular lesions and post-translational modifications leading to its dysregulation in cancer. A final section will discuss the proteins and small molecules that modulate PP2A and how these might be used to target dysregulated forms of PP2A to treat cancers and other diseases.
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Affiliation(s)
- Jaya Sangodkar
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - Caroline Farrington
- Department of Medicine and Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Kimberly McClinch
- Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew D. Galsky
- Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - David B. Kastrinsky
- Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Goutham Narla
- Department of Medicine and Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
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Yan B, Dong L, Neuzil J. Mitochondria: An intriguing target for killing tumour-initiating cells. Mitochondrion 2016; 26:86-93. [DOI: 10.1016/j.mito.2015.12.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/25/2015] [Accepted: 12/14/2015] [Indexed: 12/12/2022]
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Zhang B, Chu W, Wei P, Liu Y, Wei T. Xanthohumol induces generation of reactive oxygen species and triggers apoptosis through inhibition of mitochondrial electron transfer chain complex I. Free Radic Biol Med 2015; 89:486-97. [PMID: 26453927 DOI: 10.1016/j.freeradbiomed.2015.09.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Revised: 09/10/2015] [Accepted: 09/21/2015] [Indexed: 10/22/2022]
Abstract
Xanthohumol is a prenylflavonoid extracted from hops (Humulus lupulus). It possesses anti-cancer and anti-inflammatory activities in vitro and in vivo, and offers therapeutic benefits for treatment of metabolic syndromes. However, the precise mechanisms underlying its pharmacological effects remain to be elucidated, together with its cellular target. Here, we provide evidence that xanthohumol directly interacts with the mitochondrial electron transfer chain complex I (NADH dehydrogenase), inhibits the oxidative phosphorylation, triggers the production of reactive oxygen species, and induces apoptosis. In addition, we show that as a result of the inhibition of the mitochondrial oxidative phosphorylation, xanthohumol exposure causes a rapid decrease of mitochondrial transmembrane potential. Furthermore, we showed that xanthohumol up-regulates the glycolytic capacity in cells, and thus compensates cellular ATP generation. Dissection of the multiple steps of aerobic respiration by extracellular flux assays revealed that xanthohumol specifically inhibits the activity of mitochondrial complex I, but had little effect on that of complex II, III and IV. Inhibition of complex I by xanthohumol caused the overproduction of reactive oxygen species, which are responsible for the induction of apoptosis in cancer cells. We also found that isoxanthohumol, the structural isomer of xanthohumol, is inactive to cells, suggesting that the reactive 2-hydroxyl group of xanthohumol is crucial for its targeting to the mitochondrial complex I. Together, the remodeling of cell metabolism revealed here has therapeutic potential for the use of xanthohumol.
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Affiliation(s)
- Bo Zhang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Wei Chu
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peng Wei
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ying Liu
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, Hubei, China
| | - Taotao Wei
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
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Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, Glickson JD, Blair IA. Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. J Biol Chem 2015; 291:42-57. [PMID: 26521302 PMCID: PMC4697178 DOI: 10.1074/jbc.m115.697516] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Indexed: 11/13/2022] Open
Abstract
The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.
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Affiliation(s)
- Lili Guo
- From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and
| | - Alexander A Shestov
- Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and
| | - Andrew J Worth
- From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and
| | - Kavindra Nath
- Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and
| | - David S Nelson
- Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and
| | - Dennis B Leeper
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Jerry D Glickson
- Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and
| | - Ian A Blair
- From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and
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A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells. Sci Rep 2015; 5:13543. [PMID: 26337336 PMCID: PMC4559806 DOI: 10.1038/srep13543] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/30/2015] [Indexed: 01/24/2023] Open
Abstract
Mitochondria have recently emerged as novel targets for cancer therapy due to its important roles in fundamental cellular function. Discovery of new chemotherapeutic agents that allow for simultaneous treatment and visualization of cancer is urgent. Herein, we demonstrate a novel bifunctional mitochondria-targeted anticancer agent (FPB), exhibiting both imaging capability and anticancer activity. It can selectively accumulate in mitochondria and induce cell apoptosis. Notably, it results in much higher toxicity toward cancer cells owing to much higher uptake by cancer cells. These features make it highly attractive in cancer imaging and treatment.
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Vitamin E Analogs as Radiation Response Modifiers. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:741301. [PMID: 26366184 PMCID: PMC4558447 DOI: 10.1155/2015/741301] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 05/06/2015] [Accepted: 07/22/2015] [Indexed: 02/07/2023]
Abstract
The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.
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Affiliation(s)
- Jean-Marc Zingg
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33136-6129;
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