Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]

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 classi...

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Main Author: Tomas Koltai
Format: Article
Language:English
Published: F1000 Research Ltd 2015-03-01
Series:F1000Research
Subjects:
Online Access:http://f1000research.com/articles/4-9/v2
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spelling doaj-53ff2712bc0a4cb38503cceec9a0ba192020-11-25T02:53:51ZengF1000 Research LtdF1000Research2046-14022015-03-01410.12688/f1000research.5827.26594Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]Tomas Koltai0Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentación, Talar de Pacheco, Buenos Aires, 1618, ArgentinaObjective: 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.http://f1000research.com/articles/4-9/v2Cancer Therapeutics
collection DOAJ
language English
format Article
sources DOAJ
author Tomas Koltai
spellingShingle Tomas Koltai
Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
F1000Research
Cancer Therapeutics
author_facet Tomas Koltai
author_sort Tomas Koltai
title Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
title_short Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
title_full Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
title_fullStr Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
title_full_unstemmed Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
title_sort nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536]
publisher F1000 Research Ltd
series F1000Research
issn 2046-1402
publishDate 2015-03-01
description 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.
topic Cancer Therapeutics
url http://f1000research.com/articles/4-9/v2
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