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1
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Capuano R, Ciotti M, Catini A, Bernardini S, Di Natale C. Clinical applications of volatilomic assays. Crit Rev Clin Lab Sci 2025; 62:45-64. [PMID: 39129534 DOI: 10.1080/10408363.2024.2387038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/23/2024] [Accepted: 07/29/2024] [Indexed: 08/13/2024]
Abstract
The study of metabolomics is revealing immense potential for diagnosis, therapy monitoring, and understanding of pathogenesis processes. Volatilomics is a subcategory of metabolomics interested in the detection of molecules that are small enough to be released in the gas phase. Volatile compounds produced by cellular processes are released into the blood and lymph, and can reach the external environment through different pathways, such as the blood-air interface in the lung that are detected in breath, or the blood-water interface in the kidney that leads to volatile compounds detected in urine. Besides breath and urine, additional sources of volatile compounds such as saliva, blood, feces, and skin are available. Volatilomics traces its roots back over fifty years to the pioneering investigations in the 1970s. Despite extensive research, the field remains in its infancy, hindered by a lack of standardization despite ample experimental evidence. The proliferation of analytical instrumentations, sample preparations and methods of volatilome sampling still make it difficult to compare results from different studies and to establish a common standard approach to volatilomics. This review aims to provide an overview of volatilomics' diagnostic potential, focusing on two key technical aspects: sampling and analysis. Sampling poses a challenge due to the susceptibility of human samples to contamination and confounding factors from various sources like the environment and lifestyle. The discussion then delves into targeted and untargeted approaches in volatilomics. Some case studies are presented to exemplify the results obtained so far. Finally, the review concludes with a discussion on the necessary steps to fully integrate volatilomics into clinical practice.
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Affiliation(s)
- Rosamaria Capuano
- Department of Electronic Engineering, University of Rome Tor Vergata, Roma, Italy
- Interdepartmental Center for Volatilomics, "A. D'Amico", University of Rome Tor Vergata, Rome, Italy
| | - Marco Ciotti
- Department of Laboratory Medicine, University Hospital Tor Vergata, Rome, Italy
| | - Alexandro Catini
- Department of Electronic Engineering, University of Rome Tor Vergata, Roma, Italy
- Interdepartmental Center for Volatilomics, "A. D'Amico", University of Rome Tor Vergata, Rome, Italy
| | - Sergio Bernardini
- Interdepartmental Center for Volatilomics, "A. D'Amico", University of Rome Tor Vergata, Rome, Italy
- Department of Laboratory Medicine, University Hospital Tor Vergata, Rome, Italy
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Corrado Di Natale
- Department of Electronic Engineering, University of Rome Tor Vergata, Roma, Italy
- Interdepartmental Center for Volatilomics, "A. D'Amico", University of Rome Tor Vergata, Rome, Italy
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2
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Guan L, Xia Y, Song P, Zhao H, Zhang S, Su W, Li A, Li W. Novel bibenzyl compound 8Ae induces apoptosis and inhibits glycolysis by detaching hexokinase 2 from mitochondria in A549 cells. Bioorg Med Chem 2024; 114:117955. [PMID: 39427530 DOI: 10.1016/j.bmc.2024.117955] [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: 08/12/2024] [Revised: 10/01/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024]
Abstract
In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.
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Affiliation(s)
- Li Guan
- College of Pharmacy, Xi'an Medical University, Xi'an 710021, China
| | - Yanxin Xia
- College of Pharmacy, Xi'an Medical University, Xi'an 710021, China
| | - Pengfei Song
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Huiru Zhao
- College of Pharmacy, Xi'an Medical University, Xi'an 710021, China
| | - Shengjie Zhang
- College of Pharmacy, Xi'an Medical University, Xi'an 710021, China
| | - Wanzhen Su
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Aiyun Li
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
| | - Weize Li
- College of Pharmacy, Xi'an Medical University, Xi'an 710021, China.
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Patra SA, Sahu G, Das S, Dinda R. Recent Advances in Mitochondria-Localized Luminescent Ruthenium(II) Metallodrugs as Anticancer Agents. ChemMedChem 2023; 18:e202300397. [PMID: 37772783 DOI: 10.1002/cmdc.202300397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 09/30/2023]
Abstract
Presently, the most effective way to transport drugs specifically to mitochondria inside the cells is of pharmacophoric interest, as mitochondria are recognized as one of the most important targets for new drug design in cancer diagnosis. To date, there are many reviews covering the photophysical, photochemical, and anticancer properties of ruthenium(II) based metallodrugs owing to their high interest in biological applications. There are, however, no reviews specifically covering the mitochondria-localized luminescent Ru(II) complexes and their subsequent mitochondria-mediated anticancer activities. Therefore, this review describes the physicochemical basis for the mitochondrial accumulation of ruthenium complexes, their synthetic strategies to localize and monitor the mitochondria in living cells, and their related underlying anticancer results. Finally, we review the related areas from previous works describing the mitochondria-localized ruthenium complexes for the treatment of cancer-related diseases. Along with this, we also deliberate the perspectives and future directions for emerging more bifunctional Ru(II) complexes that can target, image, and kill tumors more efficiently in comparison with the existing mitochondria-targeted cancer therapeutics.
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Affiliation(s)
- Sushree Aradhana Patra
- Department of Chemistry, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Gurunath Sahu
- Department of Chemistry, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Sanchita Das
- Department of Chemistry, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Rupam Dinda
- Department of Chemistry, National Institute of Technology, Rourkela, 769008, Odisha, India
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4
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Leischner C, Marongiu L, Piotrowsky A, Niessner H, Venturelli S, Burkard M, Renner O. Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer. Antioxidants (Basel) 2023; 12:antiox12040916. [PMID: 37107291 PMCID: PMC10135768 DOI: 10.3390/antiox12040916] [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: 01/31/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.
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Affiliation(s)
- Christian Leischner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Luigi Marongiu
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Alban Piotrowsky
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Heike Niessner
- Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076 Tuebingen, Germany
| | - Sascha Venturelli
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Institute of Physiology, Department of Vegetative and Clinical Physiology, University of Tuebingen, Wilhelmstraße 56, 72074 Tuebingen, Germany
| | - Markus Burkard
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Olga Renner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
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Obaidi I, Blanco Fernández A, McMorrow T. Curcumin Sensitises Cancerous Kidney Cells to TRAIL Induced Apoptosis via Let-7C Mediated Deregulation of Cell Cycle Proteins and Cellular Metabolism. Int J Mol Sci 2022; 23:ijms23179569. [PMID: 36076967 PMCID: PMC9455736 DOI: 10.3390/ijms23179569] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 12/31/2022] Open
Abstract
Targeted therapies are the most attractive options in the treatment of different tumours, including kidney cancers. Such therapies have entered a golden era due to advancements in research, breakthroughs in scientific knowledge, and a better understanding of cancer therapy mechanisms, which significantly improve the survival rates and life expectancy of patients. The use of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) as an anticancer therapy has attracted the attention of the scientific community and created great excitement due to its selectivity in targeting cancerous cells with no toxic impacts on normal tissues. However, clinical studies disappointingly showed the emergence of resistance against TRAIL. This study aimed to employ curcumin to sensitise TRAIL-resistant kidney cancerous ACHN cells, as well as to gain insight into the molecular mechanisms of TRAIL sensitization. Curcumin deregulated the expression of apoptosis-regulating micro Ribonucleic Acid (miRNAs), most notably, let-7C. Transfecting ACHN cells with a let-7C antagomir significantly increased the expression of several cell cycle protein, namely beta (β)-catenin, cyclin dependent kinase (CDK)1/2/4/6 and cyclin B/D. Further, it overexpressed the expression of the two key glycolysis regulating proteins including hypoxia-inducible factor 1-alpha (HIF-1α) and pyruvate dehydrogenase kinase 1 (PDK1). Curcumin also suppressed the expression of the overexpressed proteins when added to the antagomir transfected cells. Overall, curcumin targeted ACHN cell cycle and cellular metabolism by promoting the differential expression of let-7C. To the best of our knowledge, this is the first study to mechanistically report the cancer chemosensitisation potential of curcumin in kidney cancer cells via induction of let-7C.
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Affiliation(s)
- Ismael Obaidi
- NatPro Centre for Natural Product Research, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, D02 W272 Dublin, Ireland
- College of Pharmacy, University of Babylon, Babylon 51002, Iraq
- Correspondence: (I.O.); (T.M.); Tel.: +353-8-6064-2626 (I.O.); +353-1-716-2317 (ext. 6819) (T.M.)
| | - Alfonso Blanco Fernández
- Flow Cytometry Core Technology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Tara McMorrow
- Centre for Toxicology, School of Biomedical and Biomolecular Sciences, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
- Correspondence: (I.O.); (T.M.); Tel.: +353-8-6064-2626 (I.O.); +353-1-716-2317 (ext. 6819) (T.M.)
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6
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Zeng Z, Fang C, Zhang Y, Chen CX, Zhang YF, Zhang K. Mitochondria-Targeted Nanocarriers Promote Highly Efficient Cancer Therapy: A Review. Front Bioeng Biotechnol 2021; 9:784602. [PMID: 34869294 PMCID: PMC8633539 DOI: 10.3389/fbioe.2021.784602] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 12/15/2022] Open
Abstract
Mitochondria are the primary organelles which can produce adenosine triphosphate (ATP). They play vital roles in maintaining normal functions. They also regulated apoptotic pathways of cancer cells. Given that, designing therapeutic agents that precisely target mitochondria is of great importance for cancer treatment. Nanocarriers can combine the mitochondria with other therapeutic modalities in cancer treatment, thus showing great potential to cancer therapy in the past few years. Herein, we summarized lipophilic cation- and peptide-based nanosystems for mitochondria targeting. This review described how mitochondria-targeted nanocarriers promoted highly efficient cancer treatment in photodynamic therapy (PDT), chemotherapy, combined immunotherapy, and sonodynamic therapy (SDT). We further discussed mitochondria-targeted nanocarriers’ major challenges and future prospects in clinical cancer treatment.
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Affiliation(s)
- Zeng Zeng
- Department of Medical Ultrasound, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Chao Fang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ying Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cong-Xian Chen
- Department of Medical Ultrasound, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Yi-Feng Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kun Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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7
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Fourmois L, Poyer F, Sourdon A, Naud-Martin D, Nagarajan S, Chennoufi R, Deprez E, Teulade-Fichou MP, Mahuteau-Betzer F. Modulation of Cellular Fate of Vinyl Triarylamines through Structural Fine Tuning: To Stay or Not To Stay in the Mitochondria? Chembiochem 2021; 22:2457-2467. [PMID: 34008276 DOI: 10.1002/cbic.202100168] [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: 04/08/2021] [Revised: 05/18/2021] [Indexed: 11/08/2022]
Abstract
Mitochondria are involved in many cellular pathways and dysfunctional mitochondria are linked to various diseases. Hence efforts have been made to design mitochondria-targeted fluorophores for monitoring the mitochondrial status. However, the factors that govern the mitochondria-targeted potential of dyes are not well-understood. In this context, we synthesized analogues of the TP-2Bzim probe belonging to the vinyltriphenylamine (TPA) class and already described for its capacity to bind nuclear DNA in fixed cells and mitochondria in live cells. These analogues (TP-1Bzim, TPn -2Bzim, TP1+ -2Bzim, TN-2Bzim) differ in the cationic charge, the number of vinylbenzimidazolium branches and the nature of the triaryl core. Using microscopy, we demonstrated that the cationic derivatives accumulate in mitochondria but do not reach mtDNA. Under depolarisation of the mitochondrial membrane, TP-2Bzim and TP1+ -2Bzim translocate to the nucleus in direct correlation with their strong DNA affinity. This reversible phenomenon emphasizes that these probes can be used to monitor ΔΨm variations.
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Affiliation(s)
- Laura Fourmois
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Florent Poyer
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Aude Sourdon
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Delphine Naud-Martin
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Sounderya Nagarajan
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Rahima Chennoufi
- ENS Paris-Saclay, Université Paris-Saclay, CNRS UMR8113, IDA FR3242, Laboratory of Biology and Applied Pharmacology (LBPA), 91190, Gif-sur-Yvette, France
| | - Eric Deprez
- ENS Paris-Saclay, Université Paris-Saclay, CNRS UMR8113, IDA FR3242, Laboratory of Biology and Applied Pharmacology (LBPA), 91190, Gif-sur-Yvette, France
| | - Marie-Paule Teulade-Fichou
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
| | - Florence Mahuteau-Betzer
- Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
- Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modelling for the Biology of Cancer, 91400, Orsay, France
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Abstract
Malignant tissues show a peculiar feature regarding pH: while normal tissues have a higher extracellular pH than intracellular pH, in cancer is exactly the opposite. This phenomenon is called the inversion of the pH gradient and is now considered a hallmark of malignancy. For some time, this inverted pH gradient was believed to be a secondary effect of cancer. Now, it is becoming clear that pH inversion is not an innocent consequence, but a key player in the etiopathogenesis of cancer. Therefore, addressing this issue as part of an integral treatment of neoplasia should be a necessary step for improving cancer patients' outcomes. However, the knowledge acquired in this regard through basic research has not reached bedside treatments. The most striking fact is that there are repurposed drugs and nutraceuticals with low or no toxicity that can modify the pH gradient inversion. However, these drugs have not even been tested in cancer treatment.
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Dang X, Lei S, Luo S, Hu Y, Wang J, Zhang D, Lu D, Jiang F, Fu L. Design, synthesis and biological evaluation of novel thiazole-derivatives as mitochondrial targeting inhibitors of cancer cells. Bioorg Chem 2021; 114:105015. [PMID: 34139611 DOI: 10.1016/j.bioorg.2021.105015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 01/12/2023]
Abstract
Mitochondria are pivotal energy production sources for cells to maintain necessary metabolism activities. Targeting dysfunctional mitochondrial features has been a hotspot for mitochondrial-related disease researches. Investigation with cancerous mitochondrial metabolism is a continuing concern within tumor therapy. Herein, we set out to assess the anti-cancer activities of a novel family of TPP-thiazole derivatives based on our earlier research on mitochondrial targeting agents. Specifically, we designed and synthesized a series of TPP-thiazole derivatives and revealed by the MTT assay that most synthesized compounds effectively inhibited three cancer cell lines (HeLa, PC3 and MCF-7). After structure modifications, we explored the SAR relationships and identified the most promising compound R13 (IC50 of 5.52 μM) for further investigation. In the meantime, we performed ATP production assay to assess the selected compounds inhibitory effect on HeLa cells energy production. The results displayed the test compounds significantly restrained ATP production of cancer cells. Overall, we have designed and synthesized a series of compounds which exhibited significant cytotoxicity against cancer cells and effectively inhibited mitochondrial energy production.
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Affiliation(s)
- Xin Dang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Shuwen Lei
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Shuhua Luo
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Yixin Hu
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Juntao Wang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Dongdong Zhang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Dan Lu
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Faqin Jiang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China
| | - Lei Fu
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China; SJTU-Agilent Technologies Joint Laboratory for Pharmaceutical Analysis, School of Pharmacy, Shanghai Jiao Tong University (SJTU), No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, PR China.
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10
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Mould RR, Botchway SW, Parkinson JRC, Thomas EL, Guy GW, Bell JD, Nunn AVW. Cannabidiol Modulates Mitochondrial Redox and Dynamics in MCF7 Cancer Cells: A Study Using Fluorescence Lifetime Imaging Microscopy of NAD(P)H. Front Mol Biosci 2021; 8:630107. [PMID: 34046425 PMCID: PMC8144465 DOI: 10.3389/fmolb.2021.630107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/16/2021] [Indexed: 12/23/2022] Open
Abstract
The cannabinoid, cannabidiol (CBD), is part of the plant's natural defense system that when given to animals has many useful medicinal properties, including activity against cancer cells, modulation of the immune system, and efficacy in epilepsy. Although there is no consensus on its precise mode of action as it affects many cellular targets, CBD does appear to influence mitochondrial function. This would suggest that there is a cross-kingdom ability to modulate stress resistance systems that enhance homeostasis. As NAD(P)H autofluorescence can be used as both a metabolic sensor and mitochondrial imaging modality, we assessed the potential of this technique to study the in vitro effects of CBD using 2-photon excitation and fluorescence lifetime imaging microscopy (2P-FLIM) of NAD(P)H against more traditional markers of mitochondrial morphology and cellular stress in MCF7 breast cancer cells. 2P-FLIM analysis revealed that the addition of CBD induced a dose-dependent decrease in bound NAD(P)H, with 20 µM treatments significantly decreased the contribution of bound NAD(P)H by 14.6% relative to the control (p < 0.001). CBD also increased mitochondrial concentrations of reactive oxygen species (ROS) (160 ± 53 vs. 97.6 ± 4.8%, 20 µM CBD vs. control, respectively, p < 0.001) and Ca2+ (187 ± 78 vs. 105 ± 10%, 20 µM CBD vs. the control, respectively, p < 0.001); this was associated with a significantly decreased mitochondrial branch length and increased fission. These are all suggestive of mitochondrial stress. Our results support the use of NAD(P)H autofluorescence as an investigative tool and provide further evidence that CBD can modulate mitochondrial function and morphology in a dose-dependent manner, with clear evidence of it inducing oxidative stress at higher concentrations. This continues to support emerging data in the literature and may provide further insight into its overall mode of action, not only in cancer, but potentially its function in the plant and why it can act as a medicine.
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Affiliation(s)
- Rhys Richard Mould
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | - Stanley W. Botchway
- Central Laser Facility, Science and Technology Facilities Council, UKRI, Rutherford Appleton Laboratory, Harwell Campus, Oxford, United Kingdom
| | - James R. C. Parkinson
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | - Elizabeth Louise Thomas
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | | | - Jimmy D. Bell
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | - Alistair V. W. Nunn
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
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11
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Zeng L, Sirbu D, Waddell PG, Tkachenko NV, Probert MR, Benniston AC. Hydrogen peroxide assisted photorelease of an anthraquinone-based ligand from [Ru(2,2'-bipyridine) 2(9,10-dioxo-9,10-dihydroanthracen-1-olate)]Cl in aqueous solution. Dalton Trans 2020; 49:13243-13252. [PMID: 32845949 DOI: 10.1039/d0dt02339f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A new class of light-activated ruthenium(ii) complex was designed as a potential blocker of biological functioning, especially for targeting redox reactions within mitochondria under light activation. Based on our concepts the complex [Ru(bipy)2(1-hydroxyanthra-9,10 quinone)]Cl (RU1) was prepared and studied to understand the preliminary reaction mechanisms and its excited state behaviour through a series of stability tests, electrochemistry, UV-Visible kinetics and femtosecond transient absorption spectroscopy experiments. Under white light in the presence of H2O2 two different reactions (fast and slow) appear to take place. The complex loses the quinone-based ligand and a resulting Ru(iii) or Ru(v) species is produced. The complex RU1 shows potential to consume H2O2 from the one carbon metabolism in mitochondria, and hence may cut the energy cycle pathway of tumor cells.
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Affiliation(s)
- L Zeng
- Molecular Photonics Laboratory, Chemistry-School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
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12
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Zhu YX, Jia HR, Gao G, Pan GY, Jiang YW, Li P, Zhou N, Li C, She C, Ulrich NW, Chen Z, Wu FG. Mitochondria-acting nanomicelles for destruction of cancer cells via excessive mitophagy/autophagy-driven lethal energy depletion and phototherapy. Biomaterials 2020; 232:119668. [DOI: 10.1016/j.biomaterials.2019.119668] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/01/2019] [Accepted: 12/04/2019] [Indexed: 12/18/2022]
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13
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Jeena M, Kim S, Jin S, Ryu JH. Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy. Cancers (Basel) 2019; 12:cancers12010004. [PMID: 31861339 PMCID: PMC7016936 DOI: 10.3390/cancers12010004] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/06/2019] [Accepted: 12/16/2019] [Indexed: 02/07/2023] Open
Abstract
The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.
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14
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O'Farrell NJ, Phelan JJ, Feighery R, Doyle B, Picardo SL, Ravi N, O'Toole D, Reynolds JV, O'Sullivan J. Differential Expression Profiles of Oxidative Stress Levels, 8-oxo-dG and 4-HNE, in Barrett's Esophagus Compared to Esophageal Adenocarcinoma. Int J Mol Sci 2019; 20:ijms20184449. [PMID: 31509954 PMCID: PMC6770156 DOI: 10.3390/ijms20184449] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/03/2019] [Indexed: 12/22/2022] Open
Abstract
Barrett’s esophagus (BE), a chronic inflammatory condition, is the leading risk factor for esophageal adenocarcinoma (EAC). In inflammation to cancer pathways, oxidative stress profiles have been linked to cancer progression. However, the relevance of oxidative stress profiles along the BE-disease sequence remains to be elucidated. In this study, markers of oxidative stress; DNA adducts (8-oxo-dG) and lipoperoxidation (4-HNE), and markers of proliferation (Ki67) were measured in patient biopsies representing the BE-disease sequence. Differences in expression of these markers in Barrett’s patients with cancer-progression and non-progression were examined. Proliferation was reduced in Barrett’s specialized intestinal metaplasia (SIM) compared with EAC (p < 0.035). Correcting for cell proliferation levels, a confounding factor, linked to oxidative stress profiles, SIM demonstrated increased levels of 8-oxo-dG and 4-HNE (p < 0.05) compared with EAC. Longitudinal analysis of Barrett’s patients demonstrated decreased levels of 8-oxo-dG in SIM cancer progression (p < 0.05). BE is an environment of increased oxidative stress and inflammation. Patients with progressive disease demonstrated reduced oxidative stress levels in 8-oxo-dG. Perhaps these alterations facilitate Barrett’s progression, whereas in non-progressive disease, cells follow the rules of increased oxidative stress ultimately triggers cell apoptosis, thereby preventing propagation and survival.
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Affiliation(s)
- Naoimh J O'Farrell
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - James J Phelan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Ronan Feighery
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Brendan Doyle
- Department of Histopathology, St. James' Hospital, Dublin 8, Ireland
| | - Sarah L Picardo
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Narayanasamy Ravi
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Dermot O'Toole
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James' Hospital, Dublin 8, Ireland
| | - John V Reynolds
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland.
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15
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Mallick S, Song SJ, Bae Y, Choi JS. Self-assembled nanoparticles composed of glycol chitosan-dequalinium for mitochondria-targeted drug delivery. Int J Biol Macromol 2019; 132:451-460. [DOI: 10.1016/j.ijbiomac.2019.03.215] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 03/17/2019] [Accepted: 03/28/2019] [Indexed: 12/13/2022]
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16
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Liu M, Li Y, Wang G, Guo N, Liu D, Li D, Guo L, Zheng X, Yu K, Yu K, Wang C. Release of volatile organic compounds (VOCs) from colorectal cancer cell line LS174T. Anal Biochem 2019; 581:113340. [PMID: 31226253 DOI: 10.1016/j.ab.2019.06.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 06/17/2019] [Accepted: 06/17/2019] [Indexed: 12/31/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. To date, no non-invasive and specific biomarkers have been identified for the diagnosis of CRC. The analysis of volatile organic compounds (VOCs) is attracting increasing attention and provides the possibility of a non-invasive diagnosis. Solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) have been used to analyze the VOCs released from the headspace gas of LS174T (Dukes' type B colorectal adenocarcinoma) cells, arsenic trioxide (ATO)-treated LS174T cells and the blood from tumor-bearing mice. The data were processed using principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA), which showed that the levels of decanal, 2,4-dimethyl- heptane, and twelve other metabolites were significantly greater in the headspace gas of the LS174T cells and blood of tumor-bearing mice. Additionally, in vivo experiments indicated that formic acid, ethenyl ester and p-trimethylsilyloxyphenyl-(trimethylsilyloxy)trimethylsilylacrylate were consumed during tumor growth. In conclusion, VOCs such as 1-methoxy-hexane and 2,4-dimethyl-heptane could be useful diagnostic markers for CRC. Further research should focus on the potential metabolic pathways associated with these profiles.
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Affiliation(s)
- Miao Liu
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China; Department of Anesthesiology, Xuanwu Hospital Capital Medical University, Beijing, China.
| | - Yuhang Li
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China; Department of Anesthesiology, The First Affiliated Hospital Sun Yat-sen University, Guangzhou, China.
| | - Guiyue Wang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China; Department of Anesthesiology, Tianjin Medical University Cancer Hospital, Tianjin, China.
| | - Nana Guo
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Desheng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Dandan Li
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Lei Guo
- Department of Anesthesiology, Xuanwu Hospital Capital Medical University, Beijing, China.
| | - Xiaoya Zheng
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Kaili Yu
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Kaijiang Yu
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China; Department of Critical Care Medicine, The first Affiliated Hospital of Harbin Medical University, China.
| | - Changsong Wang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China.
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17
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Wu XW, Zheng Y, Wang FX, Cao JJ, Zhang H, Zhang DY, Tan CP, Ji LN, Mao ZW. Anticancer Ir III -Aspirin Conjugates for Enhanced Metabolic Immuno-Modulation and Mitochondrial Lifetime Imaging. Chemistry 2019; 25:7012-7022. [PMID: 30913329 DOI: 10.1002/chem.201900851] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 03/24/2019] [Indexed: 12/15/2022]
Abstract
The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.
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Affiliation(s)
- Xiao-Wen Wu
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Yue Zheng
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Fang-Xin Wang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Jian-Jun Cao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Hang Zhang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Dong-Yang Zhang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Cai-Ping Tan
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Liang-Nian Ji
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
| | - Zong-Wan Mao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P.R. China
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AICAR Induces Apoptosis and Inhibits Migration and Invasion in Prostate Cancer Cells Through an AMPK/mTOR-Dependent Pathway. Int J Mol Sci 2019; 20:ijms20071647. [PMID: 30987073 PMCID: PMC6480054 DOI: 10.3390/ijms20071647] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 03/21/2019] [Accepted: 03/29/2019] [Indexed: 02/07/2023] Open
Abstract
Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial–mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-β-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.
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19
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Petrus AT, Lighezan DL, Danila MD, Duicu OM, Sturza A, Muntean DM, Ionita I. Assessment of platelet respiration as emerging biomarker of disease. Physiol Res 2019; 68:347-363. [PMID: 30904011 DOI: 10.33549/physiolres.934032] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial dysfunction is currently acknowledged as a central pathomechanism of most common diseases of the 21(st) century. Recently, the assessment of the bioenergetic profile of human peripheral blood cells has emerged as a novel research field with potential applications in the development of disease biomarkers. In particular, platelets have been successfully used for the ex vivo analysis of mitochondrial respiratory function in several acute and chronic pathologies. An increasing number of studies support the idea that evaluation of the bioenergetic function in circulating platelets may represent the peripheral signature of mitochondrial dysfunction in metabolically active tissues (brain, heart, liver, skeletal muscle). Accordingly, impairment of mitochondrial respiration in peripheral platelets might have potential clinical applicability as a diagnostic and prognostic tool as well as a biomarker in treatment monitoring. The aim of this minireview is to summarize current information in the field of platelet mitochondrial dysfunction in both acute and chronic diseases.
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Affiliation(s)
- A T Petrus
- Department of Anatomy, Physiology and Pathophysiology, Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania and Department of Functional Sciences - Pathophysiology, "Victor Babes" University of Medicine and Pharmacy of Timisoara, Timisoara, Romania.
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20
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Ramanujan VK. Quantitative Imaging of Morphometric and Metabolic Signatures Reveals Heterogeneity in Drug Response of Three-Dimensional Mammary Tumor Spheroids. Mol Imaging Biol 2019; 21:436-446. [DOI: 10.1007/s11307-019-01324-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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21
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Ganapathy-Kanniappan S. Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol 2019; 53:667-682. [PMID: 30668176 DOI: 10.1080/10409238.2018.1556578] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aerobic glycolysis is the process of oxidation of glucose into pyruvate followed by lactate production under normoxic condition. Distinctive from its anaerobic counterpart (i.e. glycolysis that occurs under hypoxia), aerobic glycolysis is frequently witnessed in cancers, popularly known as the "Warburg effect", and it is one of the earliest known evidences of metabolic alteration in neoplasms. Intracellularly, aerobic glycolysis circumvents mitochondrial oxidative phosphorylation (OxPhos), facilitating an increased rate of glucose hydrolysis. This in turn enables cancer cells to successfully compete with normal cells for glucose uptake in order to maintain uninterrupted growth. In addition, evading OxPhos mitigates excessive generation/accumulation of reactive oxygen species that otherwise may be deleterious to cells. Emerging data indicate that aerobic glycolysis in cancer also promotes glutaminolysis to satisfy the precursor requirements of certain biosynthetic processes (e.g. nucleic acids). Next, the metabolic intermediates of aerobic glycolysis also feed the pentose phosphate pathway (PPP) to facilitate macromolecular biosynthesis necessary for cancer cell growth and proliferation. Extracellularly, the extrusion of the end-product of aerobic glycolysis, i.e. lactate, alters the tumor microenvironment, and impacts cancer-associated cells. Collectively, accumulating data unequivocally demonstrate that aerobic glycolysis implicates myriad of molecular and functional processes to support cancer progression. This review, in the light of recent research, dissects the molecular intricacies of its regulation, and also deliberates the emerging paradigms to target aerobic glycolysis in cancer therapy.
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Affiliation(s)
- Shanmugasundaram Ganapathy-Kanniappan
- a The Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Science , The Johns Hopkins University School of Medicine , Baltimore , MD , USA
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22
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Xiao C, Chen X, Li W, Li L, Wang L, Xie Q, Han H. Automatic Mitochondria Segmentation for EM Data Using a 3D Supervised Convolutional Network. Front Neuroanat 2018; 12:92. [PMID: 30450040 PMCID: PMC6224513 DOI: 10.3389/fnana.2018.00092] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/15/2018] [Indexed: 12/25/2022] Open
Abstract
Recent studies have supported the relation between mitochondrial functions and degenerative disorders related to ageing, such as Alzheimer's and Parkinson's diseases. Since these studies have exposed the need for detailed and high-resolution analysis of physical alterations in mitochondria, it is necessary to be able to perform segmentation and 3D reconstruction of mitochondria. However, due to the variety of mitochondrial structures, automated mitochondria segmentation and reconstruction in electron microscopy (EM) images have proven to be a difficult and challenging task. This paper puts forward an effective and automated pipeline based on deep learning to realize mitochondria segmentation in different EM images. The proposed pipeline consists of three parts: (1) utilizing image registration and histogram equalization as image pre-processing steps to maintain the consistency of the dataset; (2) proposing an effective approach for 3D mitochondria segmentation based on a volumetric, residual convolutional and deeply supervised network; and (3) employing a 3D connection method to obtain the relationship of mitochondria and displaying the 3D reconstruction results. To our knowledge, we are the first researchers to utilize a 3D fully residual convolutional network with a deeply supervised strategy to improve the accuracy of mitochondria segmentation. The experimental results on anisotropic and isotropic EM volumes demonstrate the effectiveness of our method, and the Jaccard index of our segmentation (91.8% in anisotropy, 90.0% in isotropy) and F1 score of detection (92.2% in anisotropy, 90.9% in isotropy) suggest that our approach achieved state-of-the-art results. Our fully automated pipeline contributes to the development of neuroscience by providing neurologists with a rapid approach for obtaining rich mitochondria statistics and helping them elucidate the mechanism and function of mitochondria.
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Affiliation(s)
- Chi Xiao
- Institute of Automation, Chinese Academy of Sciences, Beijing, China.,School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
| | - Xi Chen
- Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Weifu Li
- Faculty of Mathematics and Statistics, Hubei University, Wuhan, China
| | - Linlin Li
- Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Lu Wang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Qiwei Xie
- Institute of Automation, Chinese Academy of Sciences, Beijing, China.,Data Mining Lab, Beijing University of Technology, Beijing, China
| | - Hua Han
- Institute of Automation, Chinese Academy of Sciences, Beijing, China.,School of Future Technology, University of Chinese Academy of Sciences, Beijing, China.,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
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Ahmed MAH, Ali MH, Abbas HH, Elatrash GA, Foda AAM. Expression of TOMM34 and Its Clinicopathological Correlations in Urothelial Carcinoma of the Bladder. Pathol Oncol Res 2018; 26:411-418. [PMID: 30382527 DOI: 10.1007/s12253-018-0524-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 10/25/2018] [Indexed: 02/06/2023]
Abstract
The substantial difference between normal cells and cancer cells in terms of their energy metabolism in mitochondria provides an interesting basis for the development of novel therapeutic agents targeting energy machinery of tumour cells. TOMM34 is one of the Tom (translocase of the outer membrane of mitochondria) family that was found to be overexpressed in colorectal, hepatocellular, lung and early invasive breast carcinomas. The expression profile of mitochondrial translocases in bladder cancer compared to normal urinary bladder tissues has not been investigated yet. Therefore, the aim of the current study is to investigate the expression pattern of TOMM34 in bladder cancer tissues and explore its correlation with the clinico-pathological parameters of those cases. Sixty patients who underwent either transurethral resection or radical cystectomy for bladder cancer were included in this study with revision of all their clinicopathological data and tumor slides. Ten histologically normal urothelial biopsies were also included. Immunohistochemical staining for TOMM34 was done and semi-quantitatively scored using the modified H-score. All relations were analysed using established statistical methodologies. TOMM34 overexpression was significantly associated with high tumour stage, muscle invasion and high grade. Significant positive association was observed between TOMM34 expression and poor outcome in terms of shorter disease-specific survival. This study suggests TOMM34 as a biomarker of progression and poor prognosis in urothelial cell carcinoma patients. Furthermore, we suggest a role played by mitochondrial machinery in urothelial cell carcinoma progression, which is a potential target for the newly-discovered vaccine therapy for urothelial cell carcinoma.
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Affiliation(s)
- Mohamed A H Ahmed
- Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.,East Sussex Health Care Trust, Eastbourne District General Hospital, Eastbourne, UK
| | - Mohamed Hassan Ali
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Hashem Hafez Abbas
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Gamal Ali Elatrash
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Wu J, Li J, Wang H, Liu CB. Mitochondrial-targeted penetrating peptide delivery for cancer therapy. Expert Opin Drug Deliv 2018; 15:951-964. [PMID: 30173542 DOI: 10.1080/17425247.2018.1517750] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 08/27/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Mitochondria are promising targeting organelles for anticancer strategies; however, mitochondria are difficult for antineoplastic drugs to recognize and bind. Mitochondria-penetrating peptides (MPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into mitochondria. MPPs have combined or delivered a variety of antitumor cargoes and obviously inhibited the tumor growth in vivo and in vitro. MPPs create new opportunities to develop new treatments for cancer. AREAS COVERED We review the target sites of mitochondria and the target-penetration mechanism of MPPs, different strategies, and various additional strategies decorated MPPs for tumor cell mitochondria targeting, the decorating mattes including metabolism molecules, RNA, DNA, and protein, which exploited considered as therapeutic combined with MPPs and target in human cancer treatment. EXPERT OPINION/COMMENTARY Therapeutic selectivity that preferentially targets the mitochondrial abnormalities in cancer cells without toxic impact on normal cells still need to be deepen. Moreover, it needs appropriate study designs for a correct evaluation of the target delivery outcome and the degradation rate of the drug in the cell. Generally, it is optimistic that the advances in mitochondrial targeting drug delivery by MPPs plasticity outlined here will ultimately help to the discovery of new approaches for the prevention and treatment of cancers.
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Affiliation(s)
- Jiao Wu
- a Affiliated Ren He Hospital of China Three Gorges University , Yichang , China
- b Hubei Key Lab. of Tumor Microenvironment and Immunotherapy , China Three Gorges University , Yichang , China
- c Medical School , China Three Gorges University , Yichang , China
| | - Jason Li
- d Institute for Cell Engineering , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Hu Wang
- b Hubei Key Lab. of Tumor Microenvironment and Immunotherapy , China Three Gorges University , Yichang , China
- c Medical School , China Three Gorges University , Yichang , China
- d Institute for Cell Engineering , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Chang-Bai Liu
- b Hubei Key Lab. of Tumor Microenvironment and Immunotherapy , China Three Gorges University , Yichang , China
- c Medical School , China Three Gorges University , Yichang , China
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25
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Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma. Oncotarget 2018; 9:26868-26883. [PMID: 29928490 PMCID: PMC6003570 DOI: 10.18632/oncotarget.25525] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/17/2018] [Indexed: 12/18/2022] Open
Abstract
HCC (Hepatocellular carcinoma) cells exhibit greater metabolic plasticity than normal hepatocytes since they must survive in a dynamic microenvironment where nutrients and oxygen are often scarce. Using a metabolomic approach combined with functional in vitro and in vivo assays, we aimed to identify an HCC metabolic signature associated with increased tumorigenicity and patient mortality. Metabolite profiling of HCC Dt81Hepa1-6 cells revealed that their increased tumorigenicity was associated with elevated levels of glycolytic metabolites. Tumorigenic Dt81Hepa1-6 also had an increased ability to uptake glucose leading to a higher glycolytic flux that stemmed from an increased expression of glucose transporter GLUT-1. Dt81Hepa1-6-derived tumors displayed increased mRNA expressions of glycolytic genes, Hypoxia-inducible factor-1alpha and of Cyclin D1. HCC tumors also displayed increased energy charge, reduced antioxidative metabolites and similar fatty acid biosynthesis compared to healthy liver. Increased tumoral expression of glycolytic and hypoxia signaling pathway mRNAs was associated with decreased survival in HCC patients. In conclusion, HCC cells can rapidly alter their metabolism according to their environment and switch to the use of glucose through aerobic glycolysis to sustain their tumorigenicity and proliferative ability. Therefore, cancer metabolic reprogramming could be essential for the tumorigenicity of HCC cells during cancer initiation and invasion.
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26
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Cassim S, Raymond VA, Dehbidi-Assadzadeh L, Lapierre P, Bilodeau M. Metabolic reprogramming enables hepatocarcinoma cells to efficiently adapt and survive to a nutrient-restricted microenvironment. Cell Cycle 2018; 17:903-916. [PMID: 29633904 DOI: 10.1080/15384101.2018.1460023] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a metabolically heterogeneous cancer and the use of glucose by HCC cells could impact their tumorigenicity. Dt81Hepa1-6 cells display enhanced tumorigenicity compared to parental Hepa1-6 cells. This increased tumorigenicity could be explained by a metabolic adaptation to more restrictive microenvironments. When cultured at high glucose concentrations, Dt81Hepa1-6 displayed an increased ability to uptake glucose (P<0.001), increased expression of 9 glycolytic genes, greater GTP and ATP (P<0.001), increased expression of 7 fatty acid synthesis-related genes (P<0.01) and higher levels of Acetyl-CoA, Citrate and Malonyl-CoA (P<0.05). Under glucose-restricted conditions, Dt81Hepa1-6 used their stored fatty acids with increased expression of fatty acid oxidation-related genes (P<0.01), decreased triglyceride content (P<0.05) and higher levels of GTP and ATP (P<0.01) leading to improved proliferation (P<0.05). Inhibition of lactate dehydrogenase and aerobic glycolysis with sodium oxamate led to decreased expression of glycolytic genes, reduced lactate, GTP and ATP levels (P<0.01), increased cell doubling time (P<0.001) and reduced fatty acid synthesis. When combined with cisplatin, this inhibition led to lower cell viability and proliferation (P<0.05). This metabolic-induced tumorigenicity was also reflected in human Huh7 cells by a higher glucose uptake and proliferative capacity compared to HepG2 cells (P<0.05). In HCC patients, increased tumoral expression of Glut-1, Hexokinase II and Lactate dehydrogenase correlated with poor survival (P = 2.47E-5, P = 0.016 and P = 6.58E-5). In conclusion, HCC tumorigenicity can stem from a metabolic plasticity allowing them to thrive in a broader range of glucose concentrations. In HCC, combining glycolytic inhibitors with conventional chemotherapy could lead to improved treatment efficacy.
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Affiliation(s)
- Shamir Cassim
- a Laboratoire d'hépatologie cellulaire , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , QC , Canada
| | - Valérie-Ann Raymond
- a Laboratoire d'hépatologie cellulaire , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , QC , Canada
| | - Layla Dehbidi-Assadzadeh
- a Laboratoire d'hépatologie cellulaire , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , QC , Canada
| | - Pascal Lapierre
- a Laboratoire d'hépatologie cellulaire , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , QC , Canada.,b Département de médecine , Université de Montréal , Montréal , QC , Canada
| | - Marc Bilodeau
- a Laboratoire d'hépatologie cellulaire , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , QC , Canada.,b Département de médecine , Université de Montréal , Montréal , QC , Canada
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Targeting Mitochondrial Bioenergetics as a Therapeutic Strategy for Chronic Lymphocytic Leukemia. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2426712. [PMID: 29682155 PMCID: PMC5851432 DOI: 10.1155/2018/2426712] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 11/06/2017] [Indexed: 12/31/2022]
Abstract
Altered cellular metabolism is considered a hallmark of cancer and is fast becoming an avenue for therapeutic intervention. Mitochondria have recently been viewed as an important cellular compartment that fuels the metabolic demands of cancer cells. Mitochondria are the major source of ATP and metabolites necessary to fulfill the bioenergetics and biosynthetic demands of cancer cells. Furthermore, mitochondria are central to cell death and the main source for generation of reactive oxygen species (ROS). Overall, the growing evidence now suggests that mitochondrial bioenergetics, biogenesis, ROS production, and adaptation to intrinsic oxidative stress are elevated in chronic lymphocytic leukemia (CLL). Hence, recent studies have shown that mitochondrial metabolism could be targeted for cancer therapy. This review focuses the recent advancements in targeting mitochondrial metabolism for the treatment of CLL.
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28
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Szewczyk A, Gehl J, Daczewska M, Saczko J, Frandsen SK, Kulbacka J. Calcium electroporation for treatment of sarcoma in preclinical studies. Oncotarget 2018; 9:11604-11618. [PMID: 29545923 PMCID: PMC5837766 DOI: 10.18632/oncotarget.24352] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/25/2018] [Indexed: 01/08/2023] Open
Abstract
Calcium electroporation (CaEP) describes the use of electric pulses (electroporation) to transiently permeabilize cells to allow supraphysiological doses of calcium to enter the cytosol. Calcium electroporation has successfully been investigated for treatment of cutaneous metastases in a clinical study. This preclinical study explores the possible use of calcium electroporation for treatment of sarcoma. A normal murine muscle cell line (C2C12), and a human rhabdomyosarcoma cell line (RD) were used in the undifferentiated and differentiated state. Electroporation was performed using 8 pulses of 100 μs at 600–1000 V/cm; with calcium (0, 0.5, 1, and 5 mM). Viability was examined by MTS assay, intracellular calcium levels were measured, and expression of plasma membrane calcium ATPase (PMCA) was investigated using western blotting. Calcium/sodium exchanger (NCX1), ryanodine receptor (RyR1) expression and cytoskeleton structure (zyxin/actin) were assessed by immunofluorescence. CaEP efficiency on RD tumors was tested in vivo in immuno-deficient mice. CaEP was significantly more efficient in RD than in normal cells. Intracellular Ca2+ levels after CaEP increased significantly in RD, whereas a lower increase was seen in normal cells. CaEP caused decreased expression of PMCA and NCX1 in malignant cells and RyR1 in both cell lines whereas normal cells exhibited increased expression of NCX1 after CaEP. Calcium electroporation also affected cytoskeleton structure in malignant cells. This study showed that calcium electroporation is tolerated significantly better in normal muscle cells than sarcoma cells and as an inexpensive and simple cancer treatment this could potentially be used in connection with sarcoma surgery for local treatment.
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Affiliation(s)
- Anna Szewczyk
- Department of Animal Developmental Biology, Institute of Experimental Biology, University of Wroclaw, Wroclaw, Poland
| | - Julie Gehl
- Center for Experimental Drug and Gene Electrotransfer (CEDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Malgorzata Daczewska
- Department of Animal Developmental Biology, Institute of Experimental Biology, University of Wroclaw, Wroclaw, Poland
| | - Jolanta Saczko
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Stine Krog Frandsen
- Center for Experimental Drug and Gene Electrotransfer (CEDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Julita Kulbacka
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
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29
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Yadav S, Kujur PK, Pandey SK, Goel Y, Maurya BN, Verma A, Kumar A, Singh RP, Singh SM. Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death. Toxicol Appl Pharmacol 2018; 339:52-64. [DOI: 10.1016/j.taap.2017.12.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/03/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
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30
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Seki H, Onishi S, Asamura N, Suzuki Y, Kawamata J, Kaneno D, Hadano S, Watanabe S, Niko Y. Bright and two-photon active red fluorescent dyes that selectively move back and forth between the mitochondria and nucleus upon changing the mitochondrial membrane potential. J Mater Chem B 2018; 6:7396-7401. [DOI: 10.1039/c8tb02415d] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pyrene-based two-photon active and bright red emitters that localize between the mitochondria and nucleus in response to changes in the mitochondrial membrane potential.
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Affiliation(s)
- Hitomi Seki
- Research and Education Faculty
- Multidisciplinary Science Cluster
- Interdisciplinary Science Unit
- Kochi University
- Kochi
| | - Shozo Onishi
- Graduate School of Medicine
- Yamaguchi University
- Yoshida
- Japan
| | - Naoya Asamura
- Graduate School of Medicine
- Yamaguchi University
- Yoshida
- Japan
| | | | - Jun Kawamata
- Graduate School of Medicine
- Yamaguchi University
- Yoshida
- Japan
| | - Daisuke Kaneno
- Department of Applied Science
- Graduate School of Integrated Arts and Sciences
- Kochi University
- Nankoku City
- Japan
| | - Shingo Hadano
- Research and Education Faculty
- Multidisciplinary Science Cluster
- Interdisciplinary Science Unit
- Kochi University
- Kochi
| | - Shigeru Watanabe
- Research and Education Faculty
- Multidisciplinary Science Cluster
- Interdisciplinary Science Unit
- Kochi University
- Kochi
| | - Yosuke Niko
- Research and Education Faculty
- Multidisciplinary Science Cluster
- Interdisciplinary Science Unit
- Kochi University
- Kochi
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31
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Lin B, Fan L, Ge J, Zhang W, Zhang C, Dong C, Shuang S. A naphthalene-based fluorescent probe with a large Stokes shift for mitochondrial pH imaging. Analyst 2018; 143:5054-5060. [DOI: 10.1039/c8an01371c] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A naphthalene-based fluorescent pH probe with a pKa of 8.8 for imaging mitochondrial pH changes in live cells.
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Affiliation(s)
- Bo Lin
- College of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Li Fan
- Institute of Environmental Science
- Shanxi University
- Taiyuan 030006
- China
| | - Jinyin Ge
- College of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Wenjia Zhang
- College of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Caihong Zhang
- College of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Chuan Dong
- Institute of Environmental Science
- Shanxi University
- Taiyuan 030006
- China
| | - Shaomin Shuang
- College of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
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32
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Gu JJ, Singh A, Xue K, Mavis C, Barth M, Yanamadala V, Lenz P, Grau M, Lenz G, Czuczman MS, Hernandez-Ilizaliturri FJ. Up-regulation of hexokinase II contributes to rituximab-chemotherapy resistance and is a clinically relevant target for therapeutic development. Oncotarget 2017; 9:4020-4033. [PMID: 29423101 PMCID: PMC5790518 DOI: 10.18632/oncotarget.23425] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 11/26/2017] [Indexed: 02/07/2023] Open
Abstract
In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrial-mediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over-expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target.
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Affiliation(s)
- Juan J Gu
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Anil Singh
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Kai Xue
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Cory Mavis
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Matthew Barth
- Department of Pediatric Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Vivek Yanamadala
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Peter Lenz
- Department of Physics, Philipps-University, Marburg, Germany
| | - Michael Grau
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.,Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
| | - Georg Lenz
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.,Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
| | | | - Francisco J Hernandez-Ilizaliturri
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.,Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA
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33
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Loureiro R, Mesquita KA, Magalhães-Novais S, Oliveira PJ, Vega-Naredo I. Mitochondrial biology in cancer stem cells. Semin Cancer Biol 2017; 47:18-28. [DOI: 10.1016/j.semcancer.2017.06.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 06/24/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023]
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34
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Justus CR, Sanderlin EJ, Dong L, Sun T, Chi JT, Lertpiriyapong K, Yang LV. Contextual tumor suppressor function of T cell death-associated gene 8 (TDAG8) in hematological malignancies. J Transl Med 2017; 15:204. [PMID: 29017562 PMCID: PMC5634876 DOI: 10.1186/s12967-017-1305-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 09/30/2017] [Indexed: 12/27/2022] Open
Abstract
Background Extracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. TDAG8 is a proton-sensing G-protein-coupled receptor that can be activated by extracellular acidosis. Methods TDAG8 gene expression was analyzed by bioinformatic analyses and quantitative RT-PCR in human hematological malignancies. Retroviral transduction was used to restore TDAG8 expression in U937, Ramos and other blood cancer cells. Multiple in vitro and in vivo tumorigenesis and metastasis assays were employed to evaluate the effects of TDAG8 expression on blood cancer progression. Western blotting, immunohistochemistry and biochemical approaches were applied to elucidate the underlying mechanisms associated with the TDAG8 receptor pathway. Results TDAG8 expression is significantly reduced in human blood cancers in comparison to normal blood cells. Severe acidosis, pH 6.4, inhibited U937 cancer cell proliferation while mild acidosis, pH 6.9, stimulated its proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that Gα13/Rho signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis. Conclusions This study provides data to support the concept that TDAG8 functions as a contextual tumor suppressor down-regulated in hematological malignancies and potentiation of the TDAG8 receptor pathway may be explored as a potential anti-tumorigenic approach in blood cancers. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1305-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Calvin R Justus
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA
| | - Edward J Sanderlin
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA
| | - Lixue Dong
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA
| | - Tianai Sun
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.,Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.,Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Li V Yang
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA. .,Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
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35
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Sigston EAW, Williams BRG. An Emergence Framework of Carcinogenesis. Front Oncol 2017; 7:198. [PMID: 28959682 PMCID: PMC5603758 DOI: 10.3389/fonc.2017.00198] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 08/17/2017] [Indexed: 11/13/2022] Open
Abstract
Experimental paradigms provide the framework for the understanding of cancer, and drive research and treatment, but are rarely considered by clinicians. The somatic mutation theory (SMT), in which cancer is considered a genetic disease, has been the predominant traditional model of cancer for over 50 years. More recently, alternative theories have been proposed, such as tissue organization field theory (TOFT), evolutionary models, and inflammatory models. Key concepts within the various models have led to them being difficult to reconcile. Progressively, it has been recognized that biological systems cannot be fully explained by the physicochemical properties of their constituent parts. There is an increasing call for a 'systems' approach. Incorporating the concepts of 'emergence', 'systems', 'thermodynamics', and 'chaos', a single integrated framework for carcinogenesis has been developed, enabling existing theories to become compatible as alternative mechanisms, facilitating the integration of bioinformatics and providing a structure in which translational research can flow from both 'benchtop to bedside' and 'bedside to benchtop'. In this review, a basic understanding of the key concepts of 'emergence', 'systems', 'system levels', 'complexity', 'thermodynamics', 'entropy', 'chaos', and 'fractals' is provided. Non-linear mathematical equations are included where possible to demonstrate compatibility with bioinformatics. Twelve principles that define the 'emergence framework of carcinogenesis' are developed, with principles 1-10 encapsulating the key concepts upon which the framework is built and their application to carcinogenesis. Principle 11 relates the framework to cancer progression. Principle 12 relates to the application of the framework to translational research. The 'emergence framework of carcinogenesis' collates current paradigms, concepts, and evidence around carcinogenesis into a single framework that incorporates previously incompatible viewpoints and ideas. Any researcher, scientist, or clinician involved in research, treatment, or prevention of cancer can employ this framework.
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Affiliation(s)
- Elizabeth A W Sigston
- Department of Otorhinolaryngology, Head & Neck Surgery, Monash Health, Melbourne, VIC, Australia.,Department of Surgery, Monash Medical Centre, Monash University, Melbourne, VIC, Australia.,Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Bryan R G Williams
- Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
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36
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Castañeda-Gill JM, Ranjan AP, Vishwanatha JK. Development and Characterization of Methylene Blue Oleate Salt-Loaded Polymeric Nanoparticles and their Potential Application as a Treatment for Glioblastoma. ACTA ACUST UNITED AC 2017; 8. [PMID: 29034126 PMCID: PMC5636194 DOI: 10.4172/2157-7439.1000449] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Glioblastoma (GBM) is an aggressive, grade IV brain tumor that develops from astrocytes located within the cerebrum, resulting in poor prognosis and survival rates following an accepted treatment regimen of surgery, radiation, and temozolomide. Thus, development of new therapeutics is necessary. During the last two decades, methylene blue (MB) has received increased attention as a potential neurotherapeutic due to its duality in brain cancers and neurodegenerative diseases. While MB is capable of easily permeating the blood-brain barrier, its therapeutic concentrations in GBM are known to induce off-target cytotoxicity and thus, another mode of drug delivery must be considered. To this end, encapsulation of formerly unusable compounds into nanoparticles (NPs) made from the biodegradable/biocompatible, FDA approved co-polymer poly (lactide-co-glycolide) (PLGA) has been more commonplace when developing novel therapeutics. In this study, we formulated and characterized Pluronic F68-coated PLGA NPs containing a sodium oleate conjugate of MB (MBOS) via solvent displacement. Conjugation of sodium oleate to MB was shown to reduce its release from PLGA NPs compared to unmodified MB, leading to potential improvements in drug accumulation and therapeutic effectiveness. Our drug-loaded NP preparations, which were ~170 nm in size and had drug loading values of ~2%, were shown to reduce cell viability and cell compartment-specific, as well as overall cell, functions equivalenty, if not more so, when compared to free drug in two GBM cell lines. Following bio-distribution analysis of free MBOS compared to its nano-encapsulated counterpart, drug-loaded NPs were shown to more effectively permeate the BBB, which could lead to improvements in therapeutic effectiveness upon further examination in a tumor-bearing mouse model. Based on these results, we believe that the further development and eventual utilization of this nanoformulation could lead to an effective GBM therapy that could extend patient survival rates.
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Affiliation(s)
- J M Castañeda-Gill
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - A P Ranjan
- Institute for Molecular Medicine and Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - J K Vishwanatha
- Institute for Molecular Medicine and Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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37
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Li W, Deng H, Rao Q, Xie Q, Chen X, Han H. An automated pipeline for mitochondrial segmentation on ATUM-SEM stacks. J Bioinform Comput Biol 2017; 15:1750015. [PMID: 28610459 DOI: 10.1142/s0219720017500159] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
It is possible now to look more closely into mitochondrial physical structures due to the rapid development of electron microscope (EM). Mitochondrial physical structures play important roles in both cellular physiology and neuronal functions. Unfortunately, the segmentation of mitochondria from EM images has proven to be a difficult and challenging task, due to the presence of various subcellular structures, as well as image distortions in the sophisticated background. Although the current state-of-the-art algorithms have achieved some promising results, they have demonstrated poor performances on these mitochondria which are in close proximity to vesicles or various membranes. In order to overcome these limitations, this study proposes explicitly modelling the mitochondrial double membrane structures, and acquiring the image edges by way of ridge detection rather than by image gradient. In addition, this study also utilizes group-similarity in context to further optimize the local misleading segmentation. Then, the experimental results determined from the images acquired by automated tape-collecting ultramicrotome scanning electron microscopy (ATUM-SEM) demonstrate the effectiveness of this study's proposed algorithm.
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Affiliation(s)
- Weifu Li
- * Faculty of Mathematics and Statistics, Hubei University, Wuhan 430062, China.,† Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Hao Deng
- † Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,‡ Faculty of Information Technology, Macau, University of Science and Technology, Macau 999078, China
| | - Qiang Rao
- † Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Qiwei Xie
- † Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Xi Chen
- † Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Hua Han
- † Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,§ Future Technological College, University of Chinese Academy of Sciences, Beijing 100190, China.,¶ CBS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China
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Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS. Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J Pineal Res 2017; 62. [PMID: 28247434 DOI: 10.1111/jpi.12404] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 02/24/2017] [Indexed: 02/06/2023]
Abstract
Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant, protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitochondrial dynamics also enhances the cellular glycolytic flux and reduces mitochondrial oxygen consumption rate that potentiates ROS production. High glycolytic flux generates metabolically unfavorable milieu in hepatocytes leading to inflammation, which is abrogated by melatonin. The melatonin-mediated protection against mitochondrial dysfunction was also observed in high-fat diet (HFD)-fed mice through restoration of enzymatic activities associated with respiratory chain and TCA cycle. Subsequently, melatonin reduces hepatic fat deposition and inflammation in HFD-fed mice. Thus, melatonin disrupts the interaction between steatotic hepatocyte and stellate cells, leading to the activation of the latter to abrogate collagen deposition. Altogether, the results of the current study document that the pharmacological intervention with low dose of melatonin could abrogate lipotoxicity-mediated hepatic stellate cell activation and prevent the fibrosis progression.
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Affiliation(s)
- Nabanita Das
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Ashok Mandala
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Shamreen Naaz
- Department of Physiology, Oxidative Stress and Free Radical Biology Laboratory, University of Calcutta, University College of Science and Technology, Kolkata, India
| | - Suresh Giri
- Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India
| | - Mukul Jain
- Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India
| | - Debasish Bandyopadhyay
- Department of Physiology, Oxidative Stress and Free Radical Biology Laboratory, University of Calcutta, University College of Science and Technology, Kolkata, India
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Centre, San Antonio, TX, USA
| | - Sib Sankar Roy
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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Liu Y, Zhang P, Fang X, Wu G, Chen S, Zhang Z, Chao H, Tan W, Xu L. Near-infrared emitting iridium(iii) complexes for mitochondrial imaging in living cells. Dalton Trans 2017; 46:4777-4785. [DOI: 10.1039/c7dt00255f] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Two NIR-emitting cationic iridium(iii) complexes with phenylbenzo[g]quinoline ligands were found to selectively accumulate in mitochondria, superior photostability, low cytotoxicity. Thus they were demonstrated to have good potential as NIR-emitting mitochondrial imaging agents.
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Affiliation(s)
- Yuying Liu
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Peipei Zhang
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Xiaoqiang Fang
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Gongqing Wu
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Shuting Chen
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Zhina Zhang
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Hui Chao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry and Chemical Engineering
- Sun Yat-Sen University
- Guangzhou
- P. R. China
| | - Wenying Tan
- School of Food Science
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
| | - Li Xu
- School of Chemistry and Chemical Engineering
- Guangdong Pharmaceutical University
- Zhongshan 528458
- P. R. China
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Iwasaki K, Zheng YW, Murata S, Ito H, Nakayama K, Kurokawa T, Sano N, Nowatari T, Villareal MO, Nagano YN, Isoda H, Matsui H, Ohkohchi N. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. World J Gastroenterol 2016; 22:9765-9774. [PMID: 27956800 PMCID: PMC5124981 DOI: 10.3748/wjg.v22.i44.9765] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/05/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the anticancer mechanisms of the monoterpenoid alcohol linalool in human colon cancer cells.
METHODS The cytotoxic effect of linalool on the human colon cancer cell lines and a human fibroblast cell line was examined using the WST-8 assay. The apoptosis-inducing effect of linalool was measured using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry with Annexin V. Oxidative stress was investigated by staining for diphenyl-1-pyrenylphosphine, which is a cellular lipid peroxidation marker, and electron spin resonance spectroscopy. Sixteen SCID mice xenografted with human cancer cells were randomized into 3 groups for in vivo analysis: control and low-dose and high-dose linalool groups. The control group was administered tap water orally every 3 d. The linalool treatment groups were administered 100 or 200 μg/kg linalool solution orally for the same period. All mice were sacrificed under anesthesia 21 d after tumor inoculation, and tumors and organs were collected for immunohistochemistry using an anti-4-hydroxynonenal antibody. Tumor weights were measured and compared between groups.
RESULTS Linalool induced apoptosis of cancer cells in vitro, following the cancer-specific induction of oxidative stress, which was measured based on spontaneous hydroxyl radical production and delayed lipid peroxidation. Mice in the high-dose linalool group exhibited a 55% reduction in mean xenograft tumor weight compared with mice in the control group (P < 0.05). In addition, tumor-specific lipid peroxidation was observed in the in vivo model.
CONCLUSION Linalool exhibited an anticancer effect via cancer-specific oxidative stress, and this agent has potential for application in colon cancer therapy.
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Kelly J, Murphy JEJ. Mitochondrial tolerance to single and repeat exposure to simulated sunlight in human epidermal and dermal skin cells. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2016; 165:298-304. [PMID: 27838483 DOI: 10.1016/j.jphotobiol.2016.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/04/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sunlight represents the primary threat to mitochondrial integrity in skin given the unique nature of the mitochondrial genome and its proximity to the electron transport chain. The accumulation of mitochondrial DNA (mtDNA) mutations is a key factor in many human pathologies and this is linked to key roles of mitochondrial function in terms of energy production and cell regulation. OBJECTIVE The main objective of this study was to evaluate solar radiation induced changes in mitochondrial integrity, function and dynamics in human skin cells using a Q-Sun solar simulator to deliver a close match to the intensity of summer sunlight. METHODS Spontaneously immortalised human skin epidermal keratinocytes (HaCaT) and Human Dermal Fibroblasts (HDFn) were divided into two groups. Group A were irradiated once and Group B twice 7days apart and evaluated using cell survival, viability and mitochondrial membrane potential (MMP) and mass at 1, 4 and 7days post one exposure for Group A and 1, 4, 7 and 14days post second exposure for Group B. RESULTS Viability and survival of HaCaT and HDFn cells decreased after repeat exposure to Simulated Sunlight Irradiation (SSI) with no recovery. HDFn cells showed no loss in MMP after one or two exposures to SSI compared to HaCaT cells which showed a periodic loss of MMP after one exposure with a repeat exposure causing a dramatic decrease from which cells did not recover. Mitochondrial Mass in exposed HDFn cells was consistent with control after one or two exposures to SSI; however mitochondrial mass was significantly decreased in HaCaT cells. CONCLUSION Data presented here suggests that mitochondria in epidermal cells are more sensitive to sunlight damage compared to mitochondria in dermal cells, despite their origin, confirming a skin layer specific sensitivity to sunlight, but not as expected.
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Affiliation(s)
- J Kelly
- Mitochondrial Biology & Radiation Research Centre, Dept. of Life Sciences, Institute of Technology Sligo, Ash Lane, Sligo, Ireland.
| | - J E J Murphy
- Mitochondrial Biology & Radiation Research Centre, Dept. of Life Sciences, Institute of Technology Sligo, Ash Lane, Sligo, Ireland
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Souza TM, Rieswijk L, Beucken TVD, Kleinjans J, Jennen D. Persistent transcriptional responses show the involvement of feed-forward control in a repeated dose toxicity study. Toxicology 2016; 375:58-63. [PMID: 27765683 DOI: 10.1016/j.tox.2016.10.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 01/17/2023]
Abstract
Chemical carcinogenesis, albeit complex, often relies on modulation of transcription through activation or repression of key transcription factors. While analyzing extensive networks may hinder the biological interpretation, one may focus on dynamic network motifs, among which persistent feed-forward loops (FFLs) are known to chronically influence transcriptional programming. Here, to investigate the relevance a FFL-oriented approach in depth, we have focused on aflatoxin B1-induced transcriptomic alterations during distinct states of exposure (daily administration during 5days followed by a non-exposed period) of human hepatocytes, by exploring known interactions in human transcription. Several TF-coding genes were persistently deregulated after washout of AFB1. Oncogene MYC was identified as the prominent regulator and driver of many FFLs, among which a FFL comprising MYC/HIF1A was the most recurrent. The MYC/HIF1A FFL was also identified and validated in an independent set as the master regulator of metabolic alterations linked to initiation and progression of carcinogenesis, i.e. the Warburg effect, possibly as result of persistent intracellular alterations arising from AFB1 exposure (nuclear and mitochondrial DNA damage, oxidative stress, transcriptional activation by secondary messengers). In summary, our analysis shows the involvement of FFLs as modulators of gene expression suggestive of a carcinogenic potential even after termination of exposure.
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Affiliation(s)
- Terezinha M Souza
- Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands.
| | - Linda Rieswijk
- Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands.
| | - Twan van den Beucken
- Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands.
| | - Jos Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands.
| | - Danyel Jennen
- Department of Toxicogenomics, Maastricht University, Maastricht, 6229 ER, The Netherlands.
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Su X, Wang W, Ruan G, Liang M, Zheng J, Chen Y, Wu H, Fahey TJ, Guan M, Teng L. A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer. Int J Mol Sci 2016; 17:ijms17101594. [PMID: 27735863 PMCID: PMC5085627 DOI: 10.3390/ijms17101594] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/17/2016] [Accepted: 09/08/2016] [Indexed: 01/24/2023] Open
Abstract
Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice.
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Affiliation(s)
- Xingyun Su
- Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Weibin Wang
- Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Guodong Ruan
- Department of Oncology, the Second Hospital of Shaoxing, Shaoxing 312000, China.
| | - Min Liang
- Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Jing Zheng
- Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Ye Chen
- Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Huiling Wu
- Department of Plastic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Thomas J Fahey
- Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY 10021, USA.
| | - Minxin Guan
- Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Lisong Teng
- Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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O'Farrell NJ, Feighery R, Picardo SL, Lynam-Lennon N, Biniecka M, McGarrigle SA, Phelan JJ, MacCarthy F, O'Toole D, Fox EJ, Ravi N, Reynolds JV, O'Sullivan J. Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence. BMC Cancer 2016; 16:497. [PMID: 27431913 PMCID: PMC4950724 DOI: 10.1186/s12885-016-2544-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 07/11/2016] [Indexed: 01/10/2023] Open
Abstract
Background Barrett’s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s disease progression is under studied. Methods Using an in-vitro model representing the Barrett’s esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. Results Barrett’s metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett’s disease sequence in-vitro. Using patient in-vivo samples, Barrett’s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett’s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett’s metaplastic tissue compared with matched normal squamous epithelium. Conclusions We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s disease sequence.
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Affiliation(s)
- N J O'Farrell
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - R Feighery
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - S L Picardo
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - N Lynam-Lennon
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - M Biniecka
- Education and Research Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - S A McGarrigle
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - J J Phelan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - F MacCarthy
- Trinity Translational Medicine Institute, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - D O'Toole
- Trinity Translational Medicine Institute, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - E J Fox
- Department of Pathology, University of Washington, Seattle, WA, 98195, USA
| | - N Ravi
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - J V Reynolds
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland
| | - J O'Sullivan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
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Chisholm RH, Lorenzi T, Clairambault J. Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation. Biochim Biophys Acta Gen Subj 2016; 1860:2627-45. [PMID: 27339473 DOI: 10.1016/j.bbagen.2016.06.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/25/2016] [Accepted: 06/05/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Drug-induced drug resistance in cancer has been attributed to diverse biological mechanisms at the individual cell or cell population scale, relying on stochastically or epigenetically varying expression of phenotypes at the single cell level, and on the adaptability of tumours at the cell population level. SCOPE OF REVIEW We focus on intra-tumour heterogeneity, namely between-cell variability within cancer cell populations, to account for drug resistance. To shed light on such heterogeneity, we review evolutionary mechanisms that encompass the great evolution that has designed multicellular organisms, as well as smaller windows of evolution on the time scale of human disease. We also present mathematical models used to predict drug resistance in cancer and optimal control methods that can circumvent it in combined therapeutic strategies. MAJOR CONCLUSIONS Plasticity in cancer cells, i.e., partial reversal to a stem-like status in individual cells and resulting adaptability of cancer cell populations, may be viewed as backward evolution making cancer cell populations resistant to drug insult. This reversible plasticity is captured by mathematical models that incorporate between-cell heterogeneity through continuous phenotypic variables. Such models have the benefit of being compatible with optimal control methods for the design of optimised therapeutic protocols involving combinations of cytotoxic and cytostatic treatments with epigenetic drugs and immunotherapies. GENERAL SIGNIFICANCE Gathering knowledge from cancer and evolutionary biology with physiologically based mathematical models of cell population dynamics should provide oncologists with a rationale to design optimised therapeutic strategies to circumvent drug resistance, that still remains a major pitfall of cancer therapeutics. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
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Affiliation(s)
- Rebecca H Chisholm
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Tommaso Lorenzi
- School of Mathematics and Statistics, University of St Andrews, North Haugh, KY16 9SS, St Andrews, Scotland, United Kingdom. http://www.tommasolorenzi.com
| | - Jean Clairambault
- INRIA Paris, MAMBA team, 2, rue Simone Iff, CS 42112, 75589 Paris Cedex 12, France; Sorbonne Universités, UPMC Univ. Paris 6, UMR 7598, Laboratoire Jacques-Louis Lions, Boîte courrier 187, 4 Place Jussieu, 75252 Paris Cedex 05, France.
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Xu L, Liu YY, Chen LM, Xie YY, Liang JX, Chao H. Mitochondria-targeted ruthenium (II) polypyridyl complexes with benzofuran group for live cell imaging. J Inorg Biochem 2016; 159:82-8. [DOI: 10.1016/j.jinorgbio.2016.02.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/23/2016] [Accepted: 02/25/2016] [Indexed: 10/22/2022]
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3-Bromopyruvate and sodium citrate induce apoptosis in human gastric cancer cell line MGC-803 by inhibiting glycolysis and promoting mitochondria-regulated apoptosis pathway. Biochem Biophys Res Commun 2016; 475:37-43. [PMID: 27163639 DOI: 10.1016/j.bbrc.2016.04.151] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 04/27/2016] [Indexed: 11/20/2022]
Abstract
Cancer cells are mainly dependent on glycolysis to generate adenosine triphosphate (ATP) and intermediates required for cell growth and proliferation. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Our previously studies had found that both 3-bromopyruvate (BP) and sodium citrate (SCT) can inhibit tumor growth and proliferation in vitro and in vivo. However, the mechanism involved in the BP and SCT mediated antitumor activity is not entirely clear. In this work, it is demonstrated that BP inhibits the enzyme hexokinase (HK) activity and SCT suppresses the phosphofructokinase (PFK) activity respectively, both the two agents decrease viability, ATP generation and lactate content in the human gastric cancer cell line MGC-803. These effects are directly correlated with blockage of glycolysis. Furthermore, BP and SCT can induce the characteristic manifestations of mitochondria-regulated apoptosis, such as down-regulation of anti-apoptosis proteins Bcl-2 and Survivin, up-regulation of pro-apoptosis protein Bax, activation of caspase-3, as well as leakage of cytochrome c (Cyt-c). In summary, our results provided evidences that BP and SCT inhibit the MGC-803 cells growth and proliferation might be correlated with inhibiting glycolysis and promoting mitochondria-regulated apoptosis.
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Wen R, Banik B, Pathak RK, Kumar A, Kolishetti N, Dhar S. Nanotechnology inspired tools for mitochondrial dysfunction related diseases. Adv Drug Deliv Rev 2016; 99:52-69. [PMID: 26776231 PMCID: PMC4798867 DOI: 10.1016/j.addr.2015.12.024] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 11/29/2015] [Accepted: 12/31/2015] [Indexed: 02/07/2023]
Abstract
Mitochondrial dysfunctions are recognized as major factors for various diseases including cancer, cardiovascular diseases, diabetes, neurological disorders, and a group of diseases so called "mitochondrial dysfunction related diseases". One of the major hurdles to gain therapeutic efficiency in diseases where the targets are located in the mitochondria is the accessibility of the targets in this compartmentalized organelle that imposes barriers toward internalization of ions and molecules. Over the time, different tools and techniques were developed to improve therapeutic index for mitochondria acting drugs. Nanotechnology has unfolded as one of the logical and encouraging tools for delivery of therapeutics in controlled and targeted manner simultaneously reducing side effects from drug overdose. Tailor-made nanomedicine based therapeutics can be an excellent tool in the toolbox for diseases associated with mitochondrial dysfunctions. In this review, we present an extensive coverage of possible therapeutic targets in different compartments of mitochondria for cancer, cardiovascular, and mitochondrial dysfunction related diseases.
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Affiliation(s)
- Ru Wen
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Bhabatosh Banik
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Rakesh K Pathak
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Anil Kumar
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Nagesh Kolishetti
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States; Partikula LLC, Sunrise, FL 33326, United States
| | - Shanta Dhar
- NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, United States.
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Kaplia AA, Sorokina LV, Khyzhnyak SV. [REPROGRAMMING OF MITOCHONDRIAL ENERGY METABOLISM IN MALIGNANT NEOPLASMS]. UKRAINIAN BIOCHEMICAL JOURNAL 2016; 87:19-35. [PMID: 27025057 DOI: 10.15407/ubj87.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The novel ideas of fundamental role of mitochondria in the maintenance of viability of malignant cells have been reviewed. The modern state of research is considered in detail, including: mitochondrial control of the cellular redox state, sites of reactive oxygen species (ROS) production in inner mitochondrial membrane and antioxidant protection systems. Specificities of the structural-functional mitochondrial remodelling in malignant tumors, the mechanisms of the energy metabolism reprogramming, enhancement of the ROS production and adaptation to the hypoxic conditions and metabolic stress are analyzed. The available data including our research on transplanted tumors indicate that cytotoxic action of sodium dichloroacetate (the inhibitor of pyruvate dehydrogenase kinase) depends on biological properties of tumors and intensity of structural-functional mitochondrial rearrangement. Dichloroacetate turned out to be effective for sarcoma 37, but not for Lewis lung carcinoma.
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50
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Fodor T, Szántó M, Abdul-Rahman O, Nagy L, Dér Á, Kiss B, Bai P. Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK) and FOXO1. PLoS One 2016; 11:e0150232. [PMID: 26919657 PMCID: PMC4769015 DOI: 10.1371/journal.pone.0150232] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 02/10/2016] [Indexed: 12/17/2022] Open
Abstract
Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.
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Affiliation(s)
- Tamás Fodor
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
| | - Magdolna Szántó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Debrecen, H-4032, Hungary
| | - Omar Abdul-Rahman
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Debrecen, H-4032, Hungary
| | - Lilla Nagy
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Debrecen, H-4032, Hungary
| | - Ádám Dér
- Department of Oncology, Section of Radiation Therapy, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
| | - Borbála Kiss
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
| | - Peter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, H-4032, Hungary
- Research Center for Molecular Medicine, University of Debrecen, Debrecen, H-4032, Hungary
- * E-mail:
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