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  1. Article: Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity.

    Koltai, Tomas

    F1000Research

    2015  Volume 4, Page(s) 9

    Abstract: Objective: To review the mechanisms of anti-cancer activity of nelfinavir and ... according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and ... of action were also addressed.: Conclusions: The two main mechanisms involved in anti-cancer activity are ...

    Abstract Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature.
    Methods: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed.
    Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.
    Language English
    Publishing date 2015
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2699932-8
    ISSN 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.5827.2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Oxidative Stress Mediates the Antiproliferative Effects of Nelfinavir in Breast Cancer Cells.

    Soprano, Maria / Sorriento, Daniela / Rusciano, Maria Rosaria / Maione, Angela Serena / Limite, Gennaro / Forestieri, Pietro / D'Angelo, Dario / D'Alessio, Matteo / Campiglia, Pietro / Formisano, Pietro / Iaccarino, Guido / Bianco, Roberto / Illario, Maddalena

    PloS one

    2016  Volume 11, Issue 6, Page(s) e0155970

    Abstract: ... its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity ... activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS ... ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability ...

    Abstract The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability by inducing apoptosis and necrosis, without affecting primary normal breast cells. The antitumor activity of nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to cancer cells. Nelfinavir treated tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by nelfinavir in breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for breast cancer therapy.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation/drug effects ; Female ; HIV Protease Inhibitors/pharmacology ; Humans ; Nelfinavir/pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured
    Chemical Substances Antineoplastic Agents ; HIV Protease Inhibitors ; Reactive Oxygen Species ; Nelfinavir (HO3OGH5D7I)
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0155970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Nelfinavir and other protease inhibitors in cancer

    Tomas Koltai

    F1000Research, Vol

    mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]

    2015  Volume 4

    Abstract: Objective: To review the mechanisms of anti-cancer activity of nelfinavir and ... according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and ... of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are ...

    Abstract Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature. Methods: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.
    Keywords Cancer Therapeutics ; Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2015-03-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress.

    Pyrko, Peter / Kardosh, Adel / Wang, Weijun / Xiong, Wenyong / Schönthal, Axel H / Chen, Thomas C

    Cancer research

    2007  Volume 67, Issue 22, Page(s) 10920–10928

    Abstract: HIV type 1 (HIV-1) protease inhibitors (PI) have been shown to have anticancer activity in non-HIV ... inhibition of proteasome activity, and subsequent accumulation of misfolded proteins. Inhibition of glioma growth via ESR ... nelfinavir and atazanavir cause cell death in various malignant glioma cell lines in vitro. The underlying ...

    Abstract HIV type 1 (HIV-1) protease inhibitors (PI) have been shown to have anticancer activity in non-HIV-associated human cancer cells. The underlying mechanism of this effect is unclear. Here, we show that the PIs nelfinavir and atazanavir cause cell death in various malignant glioma cell lines in vitro. The underlying mechanism of this antitumor effect involves the potent stimulation of the endoplasmic reticulum (ER) stress response (ESR), as indicated by increased expression of two ESR markers, GRP78 and CHOP, and activation of ESR-associated caspase-4. Induction of ESR seems to play a central role in PI-induced cell death because small interfering RNA-mediated knockdown of the protective ER chaperone GRP78 sensitizes cells; whereas knockdown of proapoptotic caspase-4 protects cells from PI-induced cell death. Furthermore, the treatment of cells with PIs leads to aggresome formation and accumulation of polyubiquitinated proteins, implying proteasome inhibition. Thus, our results support a model whereby PIs cause tumor cell death via triggering of the ESR, inhibition of proteasome activity, and subsequent accumulation of misfolded proteins. Inhibition of glioma growth via ESR takes place in the in vivo setting as well, as nelfinavir inhibits the growth of xenografted human malignant glioma, with concomitant induction of the proapoptotic ER stress marker CHOP. Because ER stress has also been reported as the mechanism for insulin resistance and diabetes, our ER stress model of PI function may also explain why these drugs may induce insulin resistance as one of their most common side effects.
    MeSH term(s) Animals ; Atazanavir Sulfate ; Caspases, Initiator/metabolism ; Endoplasmic Reticulum/metabolism ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Glioma/drug therapy ; HIV Protease Inhibitors/pharmacology ; Heat-Shock Proteins/metabolism ; Humans ; Male ; Mice ; Mice, Nude ; Molecular Chaperones/metabolism ; Nelfinavir/pharmacology ; Neoplasm Transplantation ; Oligopeptides/pharmacology ; Pyridines/pharmacology ; Transcription Factor CHOP/metabolism
    Chemical Substances DDIT3 protein, human ; Enzyme Inhibitors ; HIV Protease Inhibitors ; Heat-Shock Proteins ; Molecular Chaperones ; Oligopeptides ; Pyridines ; molecular chaperone GRP78 ; Transcription Factor CHOP (147336-12-7) ; Atazanavir Sulfate (4MT4VIE29P) ; CASP4 protein, human (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-) ; Nelfinavir (HO3OGH5D7I)
    Language English
    Publishing date 2007-11-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-07-0796
    Database MEDical Literature Analysis and Retrieval System OnLINE

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