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

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Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity
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  F1000Research Open Peer Review , Universidad de Buenos Aires Adali Pecci Argentina, University Hospital Ansgar Brüning Munich Germany Discuss this article  (0)Comments 21 REVIEW   Nelfinavir and other protease inhibitors in cancer:   mechanisms involved in anticancer activity[v2; ref status:indexed, http://f1000r.es/536] Tomas Koltai Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentación, Talar de Pacheco, Buenos Aires, 1618, Argentina Abstract  To review the mechanisms of anti-cancer activity of nelfinavir and Objective: other protease inhibitors (PIs) based on evidences reported in the publishedliterature. We extensively reviewed the literature concerning nelfinavir (NFV) Methods: as an off target anti-cancer drug and other PIs. A classification of PIs based onanti-cancer mode of action was proposed. Controversies regarding nelfinavirmode of action were also addressed. The two main mechanisms involved in anti-cancer activity are Conclusions: endoplasmic reticulum stress-unfolded protein response pathway and Aktinhibition. However there are many other effects, partially dependent andindependent 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, androgenreceptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATPconcentration and upregulation of TRAIL receptor DR5, Bax, increasedradiosensitivity, and autophagy. The end result of all these effects is slowergrowth, 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 clinicallyachievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ERstressors.Beyond the phase I trials that have been recently completed, adequatelypowered and well-designed clinical trials are needed in the various cancer typesettings, and specific trials where NFV is tested in association with other knownanti-cancer pharmaceuticals should be sought, in order to find an appropriateplace for NFV in cancer treatment.The analysis of controversies on the molecular mechanisms of NFV hints to thepossibility that NFV works in a different way in tumor cells and in hepatocytesand adipocytes.   Referee Status:  Invited Referees  version 2 published05 Mar 2015 version 1 published12 Jan 2015   12 reportreport  12 Jan 2015, :9 (doi: ) First published:4 10.12688/f1000research.5827.1 05 Mar 2015, :9 (doi: ) Latest published:4 10.12688/f1000research.5827.2 v2 Page 1 of 19F1000Research 2015, 4:9 Last updated: 05 JUN 2015  F1000Research  Tomas Koltai () Corresponding author: tkoltai@hotmail.com Koltai T. How to cite this article:Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref  2015, :9 (doi: ) status: indexed, ]http://f1000r.es/536  F1000Research 4 10.12688/f1000research.5827.2 © 2015 Koltai T. This is an open access article distributed under the terms of the , which permits Copyright: Creative Commons Attribution Licenceunrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited. Data associated with the article areavailable under the terms of the (CC0 1.0 Public domain dedication).Creative Commons Zero "No rights reserved" data waiver The author(s) declared that no grants were involved in supporting this work. Grant information:   Competing interests: No competing interests were disclosed. 12 Jan 2015, :9 (doi: ) First published:4 10.12688/f1000research.5827.1 01 Jun 2015, :9 (doi: ) First indexed:4 10.12688/f1000research.5827.2 Page 2 of 19F1000Research 2015, 4:9 Last updated: 05 JUN 2015  Abbreviations NFV: NelfinavirPI: HIV Protease InhibitorsERS: Endoplasmic reticulum stressUPR: Unfolded protein responseBCRP: Breast cancer resistance proteinFAS: Fatty Acid Synthase Introduction In March 1997, the United States Food and Drug Administration (FDA) approved Nelvinavir (NFV, brand name Viracept) for HIV treatment in humans 1 . NFV is a safe, orally available, and potent drug against HIV-1 and HIV-2 2 . This protease inhibitor (PI) was developed by the private pharmaceutical sector and was a big suc-cess in the treatment of AIDS in association with other anti-retro-viral drugs 3 . The introduction of PIs combined with HIV reverse transcriptase inhibitors started the era of HAART (highly active anti-retroviral treatment) and is nowadays the standard of care in HIV-AIDS 4 .PIs inhibit HIV-1 and HIV-2 proteases (which are aspartate pro-teases), impeding virus replication and release of infecting viral particles from diseased cells. The mechanism of action of protease inhibitors involves competitive binding to the enzyme 5 .NFV is being progressively displaced from HIV therapeutics by second generation HIV PIs, but has shown interesting off target actions in cancer.The possible use of anti-HIV drugs against cancer is not new: in the 1990s AZT (zidovudine or azidothymidine) was proposed as anti-neoplastic drug, but clinical trials did not confirm the preliminary good results obtained in vitro 6 .That HIV PIs target other molecules besides the HIV protease is quite evident if we examine adverse effects like insulin resistance and lipodystrophy. These and other evidences such as inhibition of tumor cell production of cytokines, anti-angiogenesis, induction of apoptosis and others, suggest off targets effects for PIs, and hints to the concept of a new class of drugs against cancer with multiple anti-cancer effects 6 .NFV, the most important anti-cancer drug of the PI family, if repur-posed for cancer treatment, would have an important advantage: it has been used for more than 15 years in HIV treatment and its safety, pharmacokinetics, and adverse events are well known. Seri-ous adverse events are not common with the exception of diarrhea when used at high doses.Research on NFV as a potentially useful drug for cancer treatment 6  started in 2009.In this article, we thoroughly review the literature published in this matter and analyze mainly the anti-cancer mechanisms of action of NFV.Certain controversies regarding NFV activity in lipid metabolism will be considered in depth. Evidences of nelfinavir anti-cancer activity A partial response of Kaposi’s sarcoma patients to PIs was pub-lished in 1998 7  and good results with regression (six complete responses out of 10 patients) 8 . In 1999 Niehues et al. 9  published complete regression of Kaposi’s sarcoma in a child treated with highly active anti-retroviral therapy (HAART). Sgadari et al.  (2003) described also the inhibition of Kaposi’s sarcoma with protease inhibitors and they also mention that these drugs can antagonize vital properties of tumor cells like growth, invasion, tissue remodelling, angiogenesis and survival. They consider these effects to be a consequence of inhibition of invasion, matrix metal-loprotease, proteasome and NF- k  B signaling 10 . The possible mech-anisms of PIs off target activity on tumor cells were described by pioneering work of Schmidtke et al.  in 1999 11 : they observed that ritonavir was a modulator of proteasomal activity, allowed normal proliferation when used at low concentrations, but affected protein degradation when present at higher concentrations, and cell cycle was arrested.Ikezoe et al. 12  described that protease inhibitors increased cellular growth inhibition of all transretinoic acid (ATRA) on cell cultures of myelocitytic leukaemia lines. Protease inhibitors also increased differentiation of acute myeloid leukemia cell lines.In 2004, Ikezoe 13  described the mechanisms involved in anti-cancer activity of protease inhibitors in myeloma cells.The mechanisms involved in PIs anti-cancer activity are summa-rized in chronological order on Table 1. Nelfinavir and the ERS-UPR pathway NFV inhibits the proteases S1P and S2P that are involved in SREBP-1 maturation and other proteases necessary for protein maturation and folding (yet not fully identified) in the endothelial reticulum 49 .Activation of the unfolded protein response (UPR) starts in the ER when abnormal accumulation of protein is detected 57 . This was investigated thoroughly in yeasts where detection of abnormal protein occurs through Ire1p/Ern1p-mediated signaling from the ER (in mammals there are three sensor proteins IRE1 α , PERK and ATF6 58 ). UPR activation leads to the specific removal of 252 nucle-otides intron from a precursor mRNA of the transcription factor HAC-1p, and the resulting mature mRNA HAC-1p is translated to produce active HAC-1p . This transcription factor translocates to the nucleus and promotes the transcription of chaperones like GRP78 that facilitates removal of abnormal proteins from the ER through retrotranslocation and final disposal by the ubiquitin-proteasome pathway 59 .HAC1 precursor mRNA is constitutively expressed but not trans-lated until Ire1p/Ern1p sensor removes the necessary nucleotides.   Amendments from Version 1 In this version, a table was included listing past and ongoing clinical trials using nelfinavir in cancer treatment. See referee reports  REVISED Page 3 of 19F1000Research 2015, 4:9 Last updated: 05 JUN 2015  Table 1. Mechanisms of action of Nelvinavir and other PIs in cancer.AuthorStudy performed inResults Andre, 1998 14 Mice infected with lymphocytic choriomeningitis virus receiving ritonavir.Ritonavir inhibits chymotrypsin-like activity of the 20S proteasome. Nelfinavir does not inhibit chymotrypsin like activity.Gaedicke, 2002 15 Thymoma cells growing in syngeneic mouseRitonavir produces growth inhibition of tumors, apoptosis and affects proteosomal proteolysis. Non-transformed cell lines were relatively resistant to this activity. Accumulation of p21 (due to inhibition of proteolytic degradation).Ikezoe, 2004 13 Human Multiple Myeloma cellsGrowth arrest, apoptosis, blocked IL6 stimulated phosphorylation of STAT 3 and ERK ½. Decreased VEGF production.Sgadari, 2002 16 Kaposi sarcoma cell lesions in nude miceAnti-angiogenesis. Decrease of VEGF, bFGF. Decrease MMP2 activation.Pajonk, 2002 17 PC-3 and DU-145 prostate cancer, U373 glioblastoma, and K562 and Jurkat leukemia cellsSaquinavir inhibited activation of NF- k  B. Inhibited 20s and 26s proteasome activity. Sensitized the surviving cells to ionizing radiation. In a previous paper 18 , this same group showed that proteasome is a direct target of radiation. This explains the synergism between proteasome inhibitors and ionizing radiation.Olson, 2002 19 Cell culture of UMCC-1/VP cells which over-express MRP-1Ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1). This characteristic was not shared by other PIs.Zhou, 2004 20 Insulinoma cellsNelfinavir decreased insulin stimulated phosphorylation of IRS-2 and Akt-Thr(308) in a dose-dependent manner. For 10 micromol/L of nelfinavir, the decrease in Akt phosphorylation was 55%.Gupta, 2004 21 Human embryonic kidney cellsHIV PIs are breast cancer resistance protein inhibitors. This applies to ritonavir, saquinavir, and nelfinavir. Indinavir and amprenavir showed no inhibition on BCRP.Piccinini, 2005 22 HL60 cells incubated with and without drug.Saquinavir and nelfinavir inhibited proteasome activity at therapeutic dosages. Retroviral medication had no effect on proteasome.Gupta, 2005 23 Tumor cell culture and xenografts.Amprenavir, nelfinavir, and saquinavir inhibited Akt phosphorylation and exerted synergistic effects with radiotherapy.Yang, 2005 24 Prostate Cancer Cells: LNCaP, DU145, PC3 and LNCaP xenografts in nude miceNFV induces growth arrest and apoptosis of prostate cancer cells and blockade of androgen receptor, STAT3 and AKT. It also inhibits proliferation of LNCaP xenografts.Yang, 2006 25 NSCLC cell culture and xenografts in nude mice.NFV induces growth arrest, reduces Akt signalling, apoptosis and docetaxel sensitisation. It is responsible for up-regulation of p21, p27 and p53, down-regulation of Bcl-2 and MMP-2. NFV slowed proliferation and induced apoptosis in tumour xenografts mice without adverse systemic effects. Of the 3 PIs tested (saquinavir, ritonavir and NFV) NFV exerted the strongest inhibition on proliferation.Chow, 2006 26 Liposarcoma and non liposarcoma cell linesNFV induces apoptosis of liposarcoma cell through upregulation of SREBP-1. Authors consider that NFV is a new class of anti-liposarcoma agent.Pore, 2006 27 Glioblastoma cellsNFV decreased VEGF expression and secretion under normoxia. NFV decreases VEGF through the PI3K/Akt pathway. NFV also decreased the hypoxic induction of VEGF and the hypoxic induction of HIF-1alpha. NFV’s effect was a decreased angiogenesisPore, 2006 28 In vivo   Matrigel plug assayNFV decreases VEGF expression through the transcription factor Sp1, which regulates VEGF promoter. It down-regulates HIF-1 alfa by decreasing translation.Hampson, 2006 29 HPV transformed cervix carcinoma cellsProtease inhibitors inhibit S 26 proteasome blocking p53 degradation.Ben-Romano, 2006 30 Cell culture of 3T3-L1 adipocytesNFV induces oxidative stress that may lead to apoptosis (in adipocytes).Gupta, 2007 31 Meningioma cellsCombination therapy with imatinib and NFV potentiated anti-proliferative activity of imatinib due to decrease in survivin and increase of Bax. Thus the UPR is an intracellular signaling pathway where the ER “informs” the nucleus on the need to increase the levels of molecular chaperones and folding enzymes in order to main-tain the ER homeostasis. Therefore UPR keeps unfolded proteins in the ER until they are correctly folded before they can go to their final destination. NFV seems to produce cellular stress by accumulation of misfolded or abnormal proteins in the ER, over-whelming the normal ER protein folding machinery 60 . Chaperones bound to unfolded proteins in the ER initiate protein kinase cas-cades that inhibit translation, reverse translocation, activate ubiqui-tination enzymes, induce autophagia, and when stress is extreme, induce apoptosis. Page 4 of 19F1000Research 2015, 4:9 Last updated: 05 JUN 2015  AuthorStudy performed inResults Jiang, 2007 32 Melanoma cellsNFV produces cell cycle arrest and apoptosis through inhibition of CDK2.Jiang and Pore, 2007 33 Glioblastoma cellsNFV decreased Akt expression and enhanced radiosensitization in PTEN deficient glioblastoma cells.Gills, 2007 34 NSCLC xenografts and breast cancer resistant cell linesNFV induced caspase dependent apoptosis and also caspase independent apoptosis via ER stress and autophagy.Cuneo, 2007 35 HUVEC and tumor vascular endotheliumNFV enhance the effects of irradiation on endothelial cells.Pyrko, 2007 36 Glioblastoma cell linesEndoplasmic reticulum stress (ERS) response, as shown by increased expression of ERS markers, GRP78 and CHOP, and activation of ERS-associated caspase-4. Proteasome inhibition.De Barros, 2007 37 Human subcutaneous abdominal white adipose tissuePIs inhibited proteasome and differentiation of human preadipocytes in culture, reducing expression and production of matrix metalloproteinase 9 (MMP-9).Gills, 2008 38 60 different cancer linesNFV causes apoptosis and non-apoptotic death, ERS and autophagy. Blocks growth factor receptor activation and decreases growth factor-induced and endogenous Akt signaling. In vivo  , NFV inhibits tumor growth.Plastaras, 2008 39 Leucocytes of HIV patients receiving PI (peripheral blood biomarker assay)Decreased Akt activation at clinically achievable doses. Increases sensibility of cancer cells to radiotherapy. PIs do not increase toxicity in patients receiving radiotherapy.Brüning, 2008 40 Ovarian cancer cellsNFV upregulates TRAIL receptor DR5 which is an apoptosis inducing receptor.Giri, 2009 41 MDCKII wild-type and Bcrp1-transfected cell linesNFV may act as a breast cancer resistance protein (BCRP) inhibitor with certain substrates.Brüning, 2009 42 Ovarian cancer cell lines. Ascites samples of cancer patients.NFV induced cell death in carboplatin-sensitive resistant ovarian cancer cell lines. NFV induced formation of ER-derived vacuoles and induced up-regulation of the hsp70 heat shock family member GRP78. It induced the unfolded protein response, which causes cell cycle arrest and apoptosis. Down-regulation of cell cycle regulatory proteins, especially cyclin D3.Dewan, 2009 43 Lymphoblastoid B cells in vitro   and in mice modelRitonavir induced cell cycle arrest and apoptosis by down-regulation of cyclin D2 and surviving and suppressed transcriptional activation of NF- k  B.Wang, 2010 44 Tumor vascular networkNFV improved vascular network.Xie, 2011 45 Chemical systems biologyWeak inhibition of multiple kinases is one of the causes of NFV anti-cancer activity, without severe side effects, but still having an impact on the system. Off targets of NFV are possibly: EGFR, IGF-1R, Akt2, Abl, FGFR, CDK2, ARK2, Fak1, PDK1, Ephrin receptors. The concept behind this research is that the whole is greater than the sum of the parts.Tian, 2011 46 Glioblastoma cellsAuthors describe a pathway NFV/ERS/CHOP/up regulation of trail receptor DR5. This pathway clearly interconnects NFV with apoptosis.Brüning, 2011 47 Cervical cancer lineNFV and Bortezomib (a proteosomal inhibitor) show synergy as apoptosis inducers.Zeng, 2011 48 Pituitary adenoma cells and xenografted tumorsGrowth retardation in vivo  . Inhibition of PI3K-Akt-mTOR axis. Increased sensitivity to radiation.Guan, 2012 49 Cell cultureNFV inhibits proteolysis of SREBP-1 by inhibiting site-2 protease (S2P). Inhibition of autophagy with hydroxychloroquine enhanced apoptotic effect of nelfinavir. Accumulation of SREBP-1 produced ER stress. Decreases FAS.Bono, 2012 50 Human myeloma plasma cells and xenografted SCID miceInhibition of S26 proteasome, impaired proliferation and increased apoptosis. Decreased phosphorylation of AKT, STAT3 and ERK ½. ER stress corroborated by PERK and CHOP.Brüning, 2012 51 HeLa cells and other cancer cellsNFV and other ER stressor upregulate inhibin Beta E which shows anti-proliferative effects.Barillari, 2012 52 Cervical intraepithelial neoplasia cellsSaquinavir and ritonavir reduce MMP2 and 9, inhibiting cell invasion and growth.Timeus, 2012 53 Neuroblastoma cellsSaquinavir showed anti-proliferative and anti-invasive activity which was increased by the association with imatinib. Activation of NF- k  B was decreased. Saquinavir also exerted a pro-apoptotic activity on NB lines, which was significantly increased by the association with imatinib.Ismail, 2013 54 Hamster ovary cellsInhibits proximal insulin receptor signalling which may explain insulin resistance.Escalante, 2013 55 Myeloma cells in culture and mice xenografts.NFV is a calpain blocker. This activity enhances bortezomib (a proteosomal inhibitor) citotoxicity in vivo   and in vitro  . Drugs that block the HIV1-associated aspartyl protease also show cross reactivity with the cysteine protease calpain.Bociaga-Jasik, 2013 56 Pre-adipocytes and adipocytes in cultureSaquinavir decreased mitochondrial membrane potencial and intracellular ATP in adipocytes. Page 5 of 19F1000Research 2015, 4:9 Last updated: 05 JUN 2015
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