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Special Issue "Mitochondrial Target-Based Drug Discovery"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (15 March 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Philip Hogg

Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia
Website | E-Mail
Fax: +61 2 9385 1510
Interests: allosteric disulfide bonds; small molecule mitochondrial pharmaceuticals; cancer
Guest Editor
Dr. Pierre Dilda

Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia
Website | E-Mail
Phone: +61293858796
Interests: drug discovery; cancer drug development and pharmacology; drug resistance; medicinal chemistry; arsenical-based drugs

Special Issue Information

Dear Colleagues,

Compared to healthy cells, cancerous ones catabolize nutrients differently. Mitochondria play a central role in this altered metabolism. Mitochondria coordinate the catabolism of glucose and glutamine across the cancer cell. Disrupting this metabolism may potentially treat the disease. This special issue focuses on small molecules that inhibit the cancer cell mitochondrial metabolism, which are in pre-clinical or clinical development.

Prof. Dr. Philip Hogg
Dr. Pierre Dilda
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • cancer
  • mitochondria
  • metabolism
  • outer-mitochondrial membrane
  • inner-mitochondrial membrane
  • mitochondrial matrix

Published Papers (5 papers)

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Research

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Open AccessArticle Mitochondrial Targeted Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced Lung Injury in Mice
Pharmaceuticals 2014, 7(8), 894-912; doi:10.3390/ph7080894
Received: 28 April 2014 / Revised: 22 July 2014 / Accepted: 13 August 2014 / Published: 22 August 2014
Cited by 2 | PDF Full-text (2285 KB) | HTML Full-text | XML Full-text
Abstract
The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather
[...] Read more.
The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP) was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH) and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoIII pretreatment, but all untreated mice died prior to completing the two hour ventilation protocol, whereas all EndoIII-treated mice lived for the duration of ventilation. Thus, mitochondrial targeted DNA repair enzymes were protective against mild and moderate lung damage and they enhanced survival in the most severely injured group. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)
Open AccessArticle Condensation of Plasmid DNA Enhances Mitochondrial Association in Skeletal Muscle Following Hydrodynamic Limb Vein Injection
Pharmaceuticals 2014, 7(8), 881-893; doi:10.3390/ph7080881
Received: 15 April 2014 / Revised: 15 July 2014 / Accepted: 15 August 2014 / Published: 21 August 2014
Cited by 2 | PDF Full-text (1897 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mitochondrial gene therapy and diagnosis have the potential to provide substantial medical benefits. However, the utility of this approach has not yet been realized because the technology available for mitochondrial gene delivery continues to be a bottleneck. We previously reported on mitochondrial gene
[...] Read more.
Mitochondrial gene therapy and diagnosis have the potential to provide substantial medical benefits. However, the utility of this approach has not yet been realized because the technology available for mitochondrial gene delivery continues to be a bottleneck. We previously reported on mitochondrial gene delivery in skeletal muscle using hydrodynamic limb vein (HLV) injection. HLV injection, a useful method for nuclear transgene expression, involves the rapid injection of a large volume of naked plasmid DNA (pDNA). Moreover, the use of a condensed form of pDNA enhances the nuclear transgene expression by the HLV injection. The purpose of this study was to compare naked pDNA and condensed pDNA for mitochondrial association in skeletal muscle, when used in conjunction with HLV injection. PCR analysis showed that the use of condensed pDNA rather than naked pDNA resulted in a more effective mitochondrial association with pDNA, suggesting that the physicochemical state of pDNA plays a key role. Moreover, no mitochondrial toxicities in skeletal muscle following the HLV injection of condensed pDNA were confirmed, as evidenced by cytochrome c oxidase activity and mitochondrial membrane potential. These findings have the potential to contribute to the development for in vivo mitochondrial gene delivery system. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)
Figures

Open AccessArticle Mitochondrial FAD-linked Glycerol-3-phosphate Dehydrogenase: A Target for Cancer Therapeutics
Pharmaceuticals 2014, 7(2), 192-206; doi:10.3390/ph7020192
Received: 10 January 2014 / Revised: 29 January 2014 / Accepted: 6 February 2014 / Published: 11 February 2014
Cited by 3 | PDF Full-text (421 KB) | HTML Full-text | XML Full-text
Abstract
Imbalances in cellular redox state are frequently observed in cancer cells, and contribute significantly to cancer progression and apoptotic resistance. Hydrogen peroxide (H2O2) is one reactive oxygen species (ROS) that is produced in excess within cancer cells. In this
[...] Read more.
Imbalances in cellular redox state are frequently observed in cancer cells, and contribute significantly to cancer progression and apoptotic resistance. Hydrogen peroxide (H2O2) is one reactive oxygen species (ROS) that is produced in excess within cancer cells. In this study, we investigated the mitochondrial glycerol-3-phosphate-dependent (GPD2) ROS production in PC-3 cells and demonstrated the importance of excessive H2O2 production on their survival. By exploiting the abnormal H2O2 production of PC-3 cells, we initiated a high-throughput screening of the Canadian Compound Collection, composed of 29,586 small molecules, targeting the glycerophosphate-dependent H2O2 formation in PC-3 cells. Eighteen compounds were identified to have significant inhibitory activity. These compounds have not been previously characterized as inhibitors of the enzyme. Six of these compounds were further analyzed in PC-3 cells and dose response studies displayed an inhibitory and anti-oxidative potency that ranged from 1 µM to 30 µM. The results presented here demonstrate that inhibitors of mitochondrial GPD2 activity elicit anti-proliferative effects on cancer cells. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)

Review

Jump to: Research

Open AccessReview Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death
Pharmaceuticals 2015, 8(1), 62-106; doi:10.3390/ph8010062
Received: 11 November 2014 / Revised: 8 January 2015 / Accepted: 5 February 2015 / Published: 13 February 2015
Cited by 6 | PDF Full-text (2212 KB) | HTML Full-text | XML Full-text
Abstract
Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary
[...] Read more.
Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)
Open AccessReview Phytochemical Modulators of Mitochondria: The Search for Chemopreventive Agents and Supportive Therapeutics
Pharmaceuticals 2014, 7(9), 913-942; doi:10.3390/ph7090913
Received: 15 July 2014 / Revised: 31 July 2014 / Accepted: 13 August 2014 / Published: 4 September 2014
Cited by 8 | PDF Full-text (2964 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders
[...] Read more.
Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)

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