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HIV Protease Inhibitors: New Class of Anti-Cancer Drugs
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HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects.....atazanavir.....HIV-PI antitumour activity.....Both SQV and RTV inhibited CIN cell invasion [see article below]....Atazanavir, like nelfinavir, activates the endoplasmicreticulum stress-unfolded-protein response pathway inglioma cells.6......the anticancer potential of tipranavir anddarunavir remain unreported
Anti-HIV drugs for cancer therapeutics: back to the future?
Although nucleoside analogues, such as zidvudine, cidofovir, and ganciclovir, have very limited roles in non-HIV-related cancer treatment, non-nucleoside reverse transcriptase inhibitors, CXCR4 antagonists, and especially HIV-protease inhibitors, such as nelfinavir, hold promise as antineoplastic drugs.
Inhibition of tumour-cell invasion and angiogenesis were properties first ascribed to inhibition of HIV protease; however, they have pleiotropic antitumour effects, including inhibition of inflammatory cytokine production, proteasome activity, cell proliferation and survival, and induction of apoptosis. HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects, and other anti-HIV drugs might hold similar promise.
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70334-6/fulltext
The use of anti-HIV drugs as cancer treatments is not new. Azidothymidine was studied as an antineoplastic in the 1990s, but despite promising in vitro data, clinical trials showed little antitumour activity. HIV protease inhibitors were developed in the early 1990s, and their subsequent incorporation into highly active antiretroviral therapy (HAART) has profoundly changed the natural history of HIV infection. The potential antitumour properties of these drugs have been investigated because of their success in treating HIV-related Kaposi's sarcoma. HAART's effects on Kaposi's sarcoma did not always correlate with immune reconstitution, and activity against other solid and haematological malignancies has been established..Inhibition of tumour-cell invasion and angiogenesis were properties first ascribed to inhibition of HIV protease; however, they have pleiotropic antitumour effects, including inhibition of inflammatory cytokine production, proteasome activity, cell proliferation and survival, and induction of apoptosis. HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects, and other anti-HIV drugs might hold similar promise.........Atazanavir, like nelfinavir, activates the endoplasmicreticulum stress-unfolded-protein response pathway inglioma cells.6......the anticancer potential of tipranavir anddarunavir remain unreported.....Atazanavir, like nelfinavir, activates the endoplasmic reticulum stress-unfolded-protein response pathway in glioma cells.64......However, apart from ritonavir, only saquinavir inhibited chymotrypsin-like 20S proteasome activity, although much less efficiently, whereas no inhibition at all was observed with indinavir and nelfinavir.40 These results clearly show that, although classified together therapeutically, HIV protease inhibitors are quite distinct compounds (table 1)......Chemokines are secreted factors first described as regulators of leucocyte trafficking during inflammation.80 Chemokine CXCL12 binds its cognate cellular receptor CXCR4. Chemokine receptors CXCR4 and CCR7 are present in several types of cancer and involved in progression and metastasis.81 CXCR4 is an important co-receptor for entry of T-tropic (X4) HIV in addition to CD4 for membrane fusion and entry into the cell, and CXCR4 antagonists have been developed for HIV therapy.82 HIV drugs that target CXCR4 might, therefore, be useful in cancer therapy. AMD 3100, a small-molecule antagonist of CXCR4 in preclinical assessment for HIV treatment, inhibits intracranial growth of primary brain tumours in glioblastoma and medulloblastoma murine xenografts.83 Analogues of another CXCR4 antagonist, T140, inhibit migration of breast cancer and endothelial cells in vitro, and reduce pulmonary metastases in immunodeficient mice inoculated with breast cancer cells in vivo.84 A separate analogue of T140, 4F-bTE, had similar in-vitro inhibition of migration and invasion in bladder cancer.85 These studies show the potential application of chemokine receptor antagonists for cancer treatment (table 2).
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Researchers are investigating whether protease inhibitors could possibly be used to treat cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (in a Petri dish).[11][12] This effect has not yet been examined in humans; but studies in laboratory mice have shown that nelfinavir is able to suppress the growth of tumors in these animals, which represents a promising lead towards testing this drug in humans as well.[12]
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HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress
http://cancerres.aacrjournals.org/content/67/22/10920
Here, we show that the PIs nelfinavir and atazanavir cause cell death in various malignant glioma cell lines in vitro. .....An additional feature of protease inhibitors that might be beneficial for their potential use as anticancer agents is their ability to sensitize cancer cells to radio- and chemotherapy. For example, saquinavir, ritonavir, and indinavir were shown to potentiate the effects of all-trans-retinoic acid on human myelocytic leukemia cells ( 8), and ritonavir was shown to enhance the anticancer effects of docetaxel on prostate cancer cells in vitro and in vivo ( 9). Other investigators showed that the treatment of prostate, glioblastoma, and leukemia cells with saquinavir caused the induction of apoptosis, and that sequinavir sensitized prostate cancer cells to ionizing radiation ( 10).....Nelfinavir and amprenavir were also shown to decrease vascular endothelial growth factor (VEGF)/HIF-1α expression and angiogenesis in glioblastoma cells ( 11), whereas nelfinavir induced cell cycle arrest and apoptosis in melanoma cells ( 12). In addition, amprenavir and nelfinavir increased the effectiveness of radiotherapy in an animal xenograft tumor model....Despite growing interest in HIV-1 protease inhibitors (PI) as anti-cancer drugs, the anticancer mechanism of action of this group of chemical compounds is unknown. In our current study, we show that the PIs nelfinavir and atazanavir induce glioma cell death by triggering the ESR.
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Repositioning HIV Protease Inhibitors as Cancer Therapeutics
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682221/
PIs.... excellent candidates for further evaluation as cancer therapeutics.
Despite this wide spectrum of activity, PIs are not very potent. Most studies require ≥10 μM for cellular activity. This is relevant because pharmacokinetic studies performed in HIV patients revealed that the maximum concentrations achieved for nelfinavir were 7-9 μM. Of HIV PIs tested, nelfinavir appears to be most potent, which has led to its consideration as a lead HIV PI for cancer therapy. The recognition of PIs as broadly cytotoxic agents to cancer cells has intensified efforts to understand how PIs work, given the absence of HIV protease.
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HIV protease inhibitors to prevent progression of cervical intraepithelial neoplasia to cervical cancer: therapeutic opportunities and challenges - Editorial - (05/04/12)
Therapeutic concentrations of SQV or RTV inhibit the invasion of human primary CIN cells, and down-regulate MMP-2 and MMP-9 expression by these cells....We have previously shown that HIV-PIs efficiently inhibit the invasion of a variety of human tumour cells in vitro[21,25].....SQV or RTV inhibited EGF-promoted CIN612-7E cell invasion by -82% (P = 0.03) and -81% (P = 0.02), respectively, whereas IDV effect was less evident (Fig. 1a).
In conclusion, here we have shown in-vitro data supporting SQV or RTV effectiveness against CIN independently of their action on HIV. In addition to provide further information on the mechanisms for HIV-PI antitumour activity, and to identify markers possibly predictive of tumour response to therapy, the results described herein, together with those from our previous and recent work [21,25,30], further support the use of HIV-PIs as efficient antagonists of cancer progression, to be used alone or in combination with conventional cytotoxic drugs. Altogether, these data also recommend continuing to include HIV-PIs in HAART.
In particular, the HIV-PI indinavir (IDV), saquinavir (SQV) or ritonavir (RTV) directly impairs MMP activity, thus efficiently inhibiting tumour cell invasion and angiogenesis [21-25]. Furthermore, IDV, SQV, or RTV compromises the function of the cellular proteasome, a cytosolyc complex of enzymes regulating the turnover of intracellular proteins [24,26-29]. In doing so, SQV and RTV augment the levels of growth-suppressive proteins in tumour cells, thus leading to tumour cell growth arrest and/or apoptosis [24,26,27].
Overall, Barilleri et al. are to be commended for pointing to a potentially interesting new approach for preventing HPV-associated cancers, particularly since the proposed drugs are already in use and associated with a well known toxicity profile. Their data highlight as many challenges as opportunities, but careful selection of the appropriate therapeutic target, such as high-grade cancer precursors and the appropriate approach to dosing, such as topical therapy, might lead to promising results that will benefit both men and women at risk of HPV-associated cancers.
Both SQV and RTV inhibited CIN cell invasion, and this was paralleled by a reduced expression and proteolytic activity of the matrix metalloproteinase (MMP)-2 and 9 in treated cells. SQV and RTV also reduced CIN cell growth rate, but did not affect the invasion or growth of cells derived from highly progressed cervical carcinoma.
What are the clinical implications of their findings? On the basis of their results, the authors propose that protease inhibitors may be useful to prevent progression of CIN 3 to cervical cancer. However, evidence of the efficacy of protease inhibitors to prevent cancer in clinical studies is limited at best.
The authors rightly propose the use of protease inhibitors in HIV-uninfected individuals. As their results suggest that MMP inhibition may not inhibit cancers once they develop, they instead propose that protease inhibitors be used to treat CIN to prevent progression to cancer.However, as their results also show that at the concentrations used there was no induction of cell death or apoptosis of cells derived from a CIN lesion, CIN lesions may persist when patients are treated at doses leading to relatively low local tissue concentrations. Even if they reduce the risk of progression to cancer at these concentrations, a woman may need to take the protease inhibitor for as long as the lesion persists.
Altogether, the results described herein suggest that SQV or RTV may be effective against CIN, whereas they could lack clinical efficacy in progressed cervical carcinoma. This, and the presence or absence of HIV-PIs in HAART, could partially explain the contrasting conclusions from clinical-epidemiological studies indicating on one side a diminished risk of CIN onset or progression, and on the other side an unmodified incidence of uterine cervical carcinoma in the HAART era [9-15,54-57].
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