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Old 11-02-2011, 08:36 PM   #1
Rich66
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Nelfinavir (Viracept): available Anti HIV, anti cancer

(available Anti HIV, anti cancer, w/Gem, w/rads, w/TAM. w/chemorad in NSCLC @ 1250mg/2x/day, w/Celecoxib & Chloroquine in BC (esp triple neg), w/hydroxychloroquine in PCa)

Discount source: http://buyviraceptonline.webnode.com...line-pharmacy/




Anti-HIV’s now also anti-cancer ?

LINK

Quote:
Nelfinavir seems to exercise a broad-spectrum cancer killing effect through multiple pathways: apoptosis, necrosis and autophagy (See Clin Cancer Res 13(17): 5183-94, 2oo7), and is also noted to have antiangiogenic and immunomodulatory ability. Nelfinavir has also been shown to have radiosensitizing properties (Cancer Res. 2005 Sep 15;65(18):8256-65.) via Akt activation making it a logical addition to radiation therapy and trials using it in this fashion are underway against brain, rectal and pancreas cancers. One of the ways it works with chemo and radiation may be via disruption of the process by which hypoxia occurs by restoring proper blood flows to tumors ad making them more vulnerable to other therapies according to research by McKenna of Oxford. McKenna’s group also demonstrated as early as 2005 that Nelfinavir radiosensitized cancer cells and a small trial he conducted with nelfinavir + chemoradiation showed dramatically that 6 out of 10 patients with advanced pancreas cancer had their cancer shrank enough to be surgically removed whereas normally it would be only 1 in 10 (J Clin Oncol. 2008 Jun 1;26(16):2699-706) .
Quote:
The anti-HIV protease inhibitors have been around since 1993 and their dosage, safety and toxicity in humans are well known. Currently, multiple phase 1/2 studies are under way to evaluate the potential of nelfinavir in renal cell, rectal, lung, adenocystic, liposarcoma, brain and pancreas cancers, alone, and in combination with chemotherapy and radiotherapy and other targeted agents such as bortezomib or Velcade® and temsirolimus or Torisel®. (See current US trials here)
article on one of McKenna's pancreatic cancer patients:
Telegraph Christmas Appeal: 'Last year, I was dying of cancer. Now I might be cured'


Nov 2010

LINK

Quote:
The question was, could anything be done to switch off some of the molecular reactions that occur with cancer, and to make tumours more sensitive to radiation, so that they shrunk sufficiently that they could be removed. The group of scientists, now based at the Gray Institute for Radiation Oncology and Biology, in Oxford, decided to see whether a drug called Nelfinavir, used for the treatment of HIV, could change the way tumours responded to radiation.
Twelve patients with inoperable tumours were enrolled on a phase I trial, used to establish the safety and toxicity of a drug. They were given daily doses of the drug before radiation therapy. At the end of the trial, led by Dr Thomas Brunner, the patients were scanned again.
The research team was stunned by the results. Of 10 patients who completed the course, six were able to have previously inoperable tumours removed. Across the group, overall average survival time more than doubled. More remarkably still, in one case the combination of drug treatment and radiotherapy had eradicated every living cancer cell, with no trace of disease found by surgeons.
Cancer Biol Ther. 2009 Feb;8(3):233-5. Epub 2009 Feb 7.
Nelfinavir: a magic bullet to annihilate cancer cells?

Wu W, Zhang R, Salahub DR.

FREE TEXT

Source

Institute for Biocomplexity and Informatics, University of Calgary, Calgary, AB, CA. wuwei@ucalgary.ca

Comment on


PMID:
19333009
[PubMed - indexed for MEDLINE]


Nelfinavir may exert its anti-cancer effect via several mechanisms of action as summarized in Figure 1. Similar to most other anticancer drugs, Nelfinavir triggers caspase-dependent cell death. Bruning et al. in another study using antibody array analysis demonstrated that Nelfinavir induces TRAIL receptor (DR5) expression and can thus sensitize ovarian cancer cells to TRAIL treatment.13 Nelfinavir possesses a unique mechanism that permits the induction of caspase-independent cell death, endoplasmic reticular (ER) stress and autophagy.

Quote:
Therefore, targeting the ER stress pathway and thereby shifting the balance between survival and apoptosis using a sustained ER stress inducer (e.g., Nelfinavir) could become an attractive pharmacological strategy for suppressing cancer cells.
Another mechanism through which Nelfinavir may act against cancer is via inhibition of PI-3K/Akt activation by targeting EGFR or IGFR.7 EGFR/ERBB2/PI-3/Akt is a common survival-signaling pathway in most cancer cells including ovarian cancer.
Quote:
Nelfinavir is currently being tested in cancer patients in a phase I clinical trial that aims to evaluate the use of Nelfinavir as a single agent or in combinational treatment.11,16 The short-cut in drug development afforded by retesting in vitro the anticancer potential of drugs already FDA approved may accelerate the stream of new compounds for use in oncology, hence broadening the spectrum of alternative choices in chemotherapy. At the moment, this brute-force strategy may be our best bet in the race against the unfathomable potential of cancer cells to develop drug resistance.

PLoS Comput Biol. 2011 Apr;7(4):e1002037. Epub 2011 Apr 28.
Drug discovery using chemical systems biology: weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir.

Xie L, Evangelidis T, Xie L, Bourne PE.

Free PMC Article

Source

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America. lxie@ucsd.edu

Abstract

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent.


PMID:
21552547
[PubMed - indexed for MEDLINE]



PMCID: PMC3084228





Curr Mol Pharmacol. 2010 Jun;3(2):91-7.
New prospects for nelfinavir in non-HIV-related diseases.

Brüning A, Gingelmaier A, Friese K, Mylonas I.
Source

Ludwig-Maximilians University Munich, Department of Obstetrics/Gynecology, Campus Innenstadt, Munich, Germany. ansgar.bruening@med.uni-muenchen.de

LINK

Abstract

Nelfinavir (Viracept) was originally designed as a specific HIV protease inhibitor and, since its introduction in 1997, has served as an effective, reliable, and well-tolerated HIV drug. Although nelfinavir is being increasingly displaced by second generation HIV protease inhibitors that allow better combination treatments, it has again become a focus of interest due to an interesting paradoxical effect: nelfinavir inhibits experimentally-induced tissue degeneration or cell damage by preventing loss of the mitochondrial membrane potential, and even protects mitochondria in cancer cells but, conversely, it selectively induces a mitochondria-independent cell death mechanism in cancer cells by the so-called endoplasmic reticulum/unfolded protein stress response, allowing nelfinavir to act on otherwise chemo-resistant cancer cells. Furthermore, anti-microbial effects of nelfinavir have been described, including an efficacy against malaria, tuberculosis, and SARS. Several cancer-related clinical studies on nelfinavir as a single agent or in combination therapies have been launched and are expected to add to the usefulness of this versatile drug for cancer treatment strategies or other purposes.



PMID:
20359290
[PubMed - indexed for MEDLINE]




Breast Cancer Res. 2010;12(4):R45. Epub 2010 Jul 1.
Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells.

Brüning A, Friese K, Burges A, Mylonas I.

Free PMC Article

Source

Department of Obstetrics and Gynaecology, Campus Innenstadt, Ludwig-Maximilians-University Munich, 11 Maistrasse, Munich 80337, Germany. ansgar.bruening@med.uni-muenchen.de

Abstract

INTRODUCTION:

The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug. Several studies have shown that nelfinavir induces cell cycle arrest, endoplasmic reticulum stress, autophagy, and apoptosis in cancer cells. In the present article, the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated.

METHODS:
The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7, T47 D, MDA-MB-453, and MDA-MB-435 were tested by analysing their influence on cell viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay), apoptosis (annexin binding, poly(ADP-ribose) polymerase cleavage), autophagy (autophagy marker light chain 3B expression), endoplasmic reticulum stress (binding protein and activating transcription factor 3 expression), and the occurrence of oxidative stress (intracellular glutathione level).

RESULTS:
Nelfinavir induced apoptosis in all four breast cancer cell lines tested, although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines. The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 μg/ml to 6 μg/ml when combined with tamoxifen. At a concentration of 6 μg/ml, tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein (BiP) upregulation (MCF7, T47D), and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation (MDA-MB-453). Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study (6 μg/ml), we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32%, suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir.

CONCLUSIONS:
The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells. Moreover, the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells, suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours. We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option.



PMID: 20594311
[PubMed - indexed for MEDLINE]



Cancer Lett. 2012 Jun 1. [Epub ahead of print]
Preferential killing of triple-negative breast cancer cells in vitro and in vivo when pharmacological aggravators of endoplasmic reticulum stress are combined with autophagy inhibitors.

Thomas S, Sharma N, Golden EB, Cho H, Agarwal P, Gaffney KJ, Petasis NA, Chen TC, Hofman FM, Louie SG, Schönthal AH.

LINK
Source

Departments of Molecular Microbiology and Immunology University of Southern California, Los Angeles, California, USA.

Abstract

The cellular processes of autophagy and endoplasmic reticulum stress (ERS) appear to be interconnected, and it has been proposed that autophagy may serve to reduce ERS via removal of terminally misfolded and aggregated proteins. Conversely, there are indications that blockage of autophagy may increase ERS. Based on earlier work demonstrating that pharmacologically aggravated ERS can result in tumor cell killing, we investigated whether blockage of autophagy would enhance this effect in a therapeutically useful manner. We therefore combined chloroquine (CQ), a pharmacological inhibitor of autophagy, with other drugs known to act as ERS aggravators (ERSA), namely nelfinavir (an HIV protease inhibitor) and celecoxib (a cyclooxygenase-2 inhibitor) or its non-coxib analog 2,5-dimethyl-celecoxib (DMC), and investigated combination drug effects in a variety of breast cancer cell lines. We found that the addition of CQ resulted in synergistic enhancement of tumor cell killing by ERSA compounds, particularly in triple-negative breast cancer (TNBC) cells. This combination effect could also be confirmed in an in vivo model, where CQ boosted low-dose ERSA effects, resulting in rapid deterioration of xenografted tumors in mice. Altogether, our results indicate that combinations of an autophagy inhibitor with pharmacological ERSA (i.e., compounds that lead to ER stress aggravation) should be further explored for potential therapy of otherwise difficult-to-treat TNBC.
Copyright © 2012. Published by Elsevier Ireland Ltd.





Cancer Lett. 2009 Sep 8;282(1):87-97. Epub 2009 Apr 3.
Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress.

Cho HY, Thomas S, Golden EB, Gaffney KJ, Hofman FM, Chen TC, Louie SG, Petasis NA, Schönthal AH.

LINK

Source

Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Ave., Los Angeles, CA 90089-9094, USA.

Abstract

Moderate activity of the endoplasmic reticulum (ER) stress response system exerts anti-apoptotic function and supports tumor cell survival and chemoresistance, whereas its more severe aggravation may exceed the protective capacity of this system and turn on its pro-apoptotic module. In this study, we investigated whether the combination of two pharmacologic agents with known ability to trigger ER stress via different mechanisms would synergize and lead to enhanced tumor cell death. We combined the HIV protease inhibitor nelfinavir (Viracept) and the cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex) and investigated their combined effect on ER stress and on the viability of breast cancer cells. We found that this drug combination aggravated ER stress and caused pronounced toxicity in human breast cancer cell lines, inclusive of variants that were highly resistant to other therapeutic treatments, such as doxorubicin, paclitaxel, or trastuzumab. The anti-tumor effects of celecoxib were mimicked at increased potency by its non-coxib analog, 2,5-dimethyl-celecoxib (DMC), but were substantially weaker in the case of unmethylated-celecoxib (UMC), a derivative with superior COX-2 inhibitory efficacy. We conclude that the anti-tumor effects of nelfinavir can be enhanced by celecoxib analogs in a COX-2 independent fashion via the aggravation of ER stress, and such drug combinations should be considered as a beneficial adjunct to the treatment of drug-resistant breast cancers.



PMID:
19345476
[PubMed - indexed for MEDLINE]



Curr Opin HIV AIDS. 2008 Nov;3(6):666-75.
Repositioning HIV protease inhibitors as cancer therapeutics.

Bernstein WB, Dennis PA.

Free PMC Article

Source

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20899, USA.

Abstract

PURPOSE OF REVIEW:

Although designed to target only the HIV protease, HIV protease inhibitors induce toxicities in patients such as insulin resistance and lipodystrophy that suggest that protease inhibitors have other targets in mammalian cells. Akt controls insulin signaling and is an important target in cancer, but no Akt inhibitors are approved as cancer therapeutics. These observations have prompted the study of HIV protease inhibitors as inhibitors of Akt and possible cancer therapeutics. This review will highlight the latest advances in repositioning HIV protease inhibitors as cancer therapeutics.

RECENT FINDINGS:

Although protease inhibitors can inhibit Akt activation and the proliferation of over 60 cancer cell lines, as well as improve sensitivity to radiation or chemotherapy, these effects do not always correlate with Akt inhibition. Other important processes, such as the induction of endoplasmic reticulum stress, appear critical to the biological activity of protease inhibitors. These impressive and surprising preclinical data have prompted clinical testing of nelfinavir as a lead HIV protease inhibitor in cancer patients.

SUMMARY:

Although mechanisms of action for the antitumor effects of HIV protease inhibitors are complex, their broad spectrum of activity, minimal toxicity, and wide availability make protease inhibitors ideal candidates for repositioning as cancer therapeutics.



PMID:
19373040
[PubMed]



PMCID: PMC2682221











Clin Cancer Res. 2010 Feb 1;16(3):912-23. Epub 2010 Jan 26.
Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status.

Kimple RJ, Vaseva AV, Cox AD, Baerman KM, Calvo BF, Tepper JE, Shields JM, Sartor CI.
Source

Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA. rkimple@unch.unc.edu


Free PMC Article

Abstract

PURPOSE:

Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations.

EXPERIMENTAL DESIGN:

Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity.
RESULTS:

Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5).


CONCLUSIONS:

Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status.





Cancer Biol Ther. 2011 Oct 1;12(7):657-63. Epub 2011 Oct 1.
Nelfinavir induces radiation sensitization in pituitary adenoma cells.

Zeng J, See AP, Aziz K, Thiyagarajan S, Salih T, Gajula RP, Armour M, Phallen J, Terezakis S, Kleinberg L, Redmond K, Hales RK, Salvatori R, Quinones-Hinojosa A, Tran PT, Lim M.

LINK

Source

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, MD, USA.

Abstract

Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p< 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p< 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT-mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies.



PMID:
21811091
[PubMed - in process]


Cancer Biol Ther. 2009 Feb;8(3):226-32. Epub 2009 Feb 3.
Nelfinavir induces the unfolded protein response in ovarian cancer cells, resulting in ER vacuolization, cell cycle retardation and apoptosis.

Brüning A, Burger P, Vogel M, Rahmeh M, Gingelmaiers A, Friese K, Lenhard M, Burges A.

Free PMC Article

Source

University Hospital Munich, Department of Obstetrics/Gynecology, Maistrasse 11, München 80337, Germany. ansgar.bruening@med.uni-muenchen.de

Abstract

Proteasome inhibitors and protease inhibitors are currently being discussed to be useful to sensitize drug-resistant cancer cells to chemotherapeutic agents or to act independently as single agents on drug-resistant cancer cells. We tested the effect of the clinically applied HIV protease inhibitor nelfinavir on ovarian cancer cells. Nelfinavir efficiently induced cell death in carboplatin-sensitive (SKOV3, OV-GH-5) and carboplatin-resistant (OVCAR3, OV-GH-1) ovarian cancer cell lines as well as in cancer biopsies and ascites samples from patients with recurrent ovarian cancer. Nelfinavir significantly changed the morphology of ovarian cancer cells, resulting in formation of large ER-derived vacuoles and induced upregulation of the hsp70 heat shock family member BiP (GRP78) which accumulated within swollen ER membranes. Upregulation of BiP and phosphorylation of eIF2alpha indicated induction of the unfolded protein response, which can cause cell cycle arrest and apoptosis. Correspondingly, we observed downregulation of cell cycle regulatory proteins after nelfinavir treatment, especially that of cyclin D3, and induction of apoptosis as confirmed by annexin binding. Because nelfinavir represents an already approved drug for use in humans with HIV infection, it could rapidly be tested in clinical studies as a potential treatment strategy against drug-resistant ovarian cancer.

Comment in


PMID:
19106637
[PubMed - indexed for MEDLINE]









FEBS J. 2012 Apr 28. doi: 10.1111/j.1742-4658.2012.08619.x. [Epub ahead of print]
Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer.

Guan M, Fousek K, Chow WA.

LINK
Source

 Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA  Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.

Abstract

Nelfinavir induces apoptosis in liposarcoma by inhibiting site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. We postulate similar effects in castration-resistant prostate cancer because it exhibits a lipogenic phenotype. Nelfinavir inhibited androgen receptor activation in androgen-sensitive prostate cancer and the nuclear translocation of the fusion proteins sterol regulatory element binding protein-1 (SREBP-1)-enhanced green fluorescence protein (EGFP) and activating transcription factor 6 (ATF6)-EGFP in castration-resistant prostate cancer cells, viewed under confocal microscopy. Nelfinavir and site-1 protease (S1P) and S2P small interfering RNAs (siRNAs) reduced the proliferation of castration-resistant prostate cancer and induced apoptosis, which was opposed by autophagy. Inhibition of autophagy with hydroxychloroquine was additive to the apoptotic effect of nelfinavir. Western blotting of S1P and S2P siRNA knockdown and/or nelfinavir-treated cells confirmed the accumulation of precursor SREBP-1 and ATF6. 3,4-Dichloroisocoumarin, an S1P inhibitor, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduced the nelfinavir-treated molecular and biological phenotype. Nelfinavir-mediated inhibition of regulated intramembrane proteolysis led to the accumulation of unprocessed SREBP-1 and ATF6. This resulted in sequential endoplasmic reticulum stress, inhibition of the unfolded protein response, reduced fatty acid synthase expression and apoptosis, which was countered by autophagy. Inhibition of autophagy was at least additive to this pro-apoptotic effect. These findings provide new insights into nelfinavir-induced endoplasmic reticulum stress and cancer cell death, and lead us to propose investigating its clinical activity in castration-resistant prostate cancer. This report validates S2P as a therapeutic target in castration-resistant prostate cancer.
© 2012 City of Hope and Beckman Research Institute. Journal compilation © 2012 FEBS







Perhaps worked too quickly with radiation..HIV compromised patient?:

J Thorac Oncol. 2009 Dec;4(12):1587-9.
Marked tumor response and fatal hemoptysis during radiation for lung cancer in a human immunodeficiency virus-positive patient taking nelfinavir.

Chapman CH, Shen J, Filion EJ, Tran PT, Hara W, Asuncion A, Marko D, Wakelee H, Berry GJ, Dimmick KW, Loo BW Jr, Green J.

LINK

Source

Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA.



PMID:
20009915
[PubMed - indexed for MEDLINE]





J Thorac Oncol. 2012 Apr;7(4):709-15.
A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell lung cancer: a report of toxicities and clinical response.

Rengan R, Mick R, Pryma D, Rosen MA, Lin LL, Maity AM, Evans TL, Stevenson JP, Langer CJ, Kucharczuk J, Friedberg J, Prendergast S, Sharkoski T, Hahn SM.

LINK

Source

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. rengan@uphs.upenn.edu

Abstract

BACKGROUND:

The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).
METHODS:

Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis.
RESULTS:

Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%).
CONCLUSION:

Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.



PMID:
22425919
[PubMed - in process]



PMCID:
PMC3310889
[Available on 2013/4/1]
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Old 11-02-2011, 08:36 PM   #2
Rich66
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Location: South East Wisconsin
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Re: Nelfinavir: available Anti HIV, anti cancer

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Old 11-02-2011, 08:37 PM   #3
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Re: Nelfinavir: available Anti HIV, anti cancer

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