• 1
    Cattelan AM, Calabro ML, Aversa SM, Zanchetta M, Meneghetti F, De RA, Chieco-Bianchi L. Regression of AIDS-related Kaposi's sarcoma following antiretroviral therapy with protease inhibitors: biological correlates of clinical outcome. Eur J Cancer 1999; 35: 180915.
  • 2
    Heard I, Schmitz V, Costagliola D, Orth G, Kazatchkine MD. Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy1. AIDS 1998; 12: 145964.
  • 3
    Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy 1. AIDS 2001; 15: 2802.
  • 4
    International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000; 92: 182330.
  • 5
    Lebbe C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, Danne O, Calvo F. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma. AIDS 1998; 12: F45F49.
  • 6
    Robinson WR, Freeman D. Improved outcome of cervical neoplasia in HIV-infected women in the era of highly active antiretroviral therapy 1. AIDS Patient Care STDS 2002; 16: 615.
  • 7
    Monini P, Sgadari C, Toschi E, Barillari G, Ensoli B. Antitumour effects of antiretroviral therapy. Nat Rev Cancer 2004; 4: 86175.
  • 8
    Sgadari C, Monini P, Barillari G, Ensoli B. Use of HIV protease inhibitors to block Kaposi's sarcoma and tumour growth. Lancet Oncol 2003; 4: 53747.
  • 9
    Bower M, Powles T, Nelson M, Mandalia S, Gazzard B, Stebbing J. Highly active antiretroviral therapy and human immunodeficiency virus-associated primary cerebral lymphoma. J Natl Cancer Inst 2006; 98: 108891.
  • 10
    Grabar S, Abraham B, Mahamat A, Del GP, Rosenthal E, Costagliola D. Differential impact of combination antiretroviral therapy in preventing Kaposi's sarcoma with and without visceral involvement. J Clin Oncol 2006; 24: 340814.
  • 11
    Stebbing J, Gazzard B, Mandalia S, Teague A, Waterston A, Marvin V, Nelson M, Bower M. Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 2004; 22: 217783.
  • 12
    Stebbing J, Portsmouth S, Nelson M, Mandalia S, Kandil H, Alexander N, Davies L, Brock C, Bower M, Gazzard B. The efficacy of ritonavir in the prevention of AIDS-related Kaposi's sarcoma. Int J Cancer 2004; 108: 6313.
  • 13
    Benfield TL, Kirk O, Elbrond B, Pedersen C. Complete histological regression of Kaposi's sarcoma following treatment with protease inhibitors despite persistence of HHV-8 in lesions. Scand J Infect Dis 1998; 30: 6135.
  • 14
    Carrio M, Mazo A, Lopez-Iglesias C, Estivill X, Fillat C. Retrovirus-mediated transfer of the herpes simplex virus thymidine kinase and connexin26 genes in pancreatic cells results in variable efficiency on the bystander killing: implications for gene therapy. Int J Cancer 2001; 94: 818.
  • 15
    Gill J, Bourboulia D, Wilkinson J, Hayes P, Cope A, Marcelin AG, Calvez V, Gotch F, Boshoff C, Gazzard B. Prospective study of the effects of antiretroviral therapy on Kaposi sarcoma—associated herpes virus infection in patients with and without Kaposi sarcoma. J Acquir Immune Defic Syndr 2002; 31: 38490.
  • 16
    Heard I, Tassie JM, Kazatchkine MD, Orth G. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS 2002; 16: 1799802.
  • 17
    Kirk O, Pedersen C, Cozzi-Lepri A, Antunes F, Miller V, Gatell JM, Katlama C, Lazzarin A, Skinhoj P, Barton SE. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001; 98: 340612.
  • 18
    Martinez V, Caumes E, Gambotti L, Ittah H, Morini JP, Deleuze J, Gorin I, Katlama C, Bricaire F, Dupin N. Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer 2006; 94: 10006.
  • 19
    Nunez M, Machuca A, Soriano V, Podzamczer D, Gonzalez-Lahoz J. Clearance of human herpesvirus type 8 viraemia in HIV-1-positive patients with Kaposi's sarcoma treated with liposomal doxorubicin. Caelyx/KS Spanish Study Group 1. AIDS 2000; 14: 9139.
  • 20
    Torre-Cisneros J, Pozo F, Serrano R, Vidal E, Rivero A, Tenorio A. Patterns of lymphotropic herpesvirus viraemia in HIV-infected patients with Kaposi's sarcoma treated with highly active antiretroviral therapy and liposomal daunorubicin. AIDS 2000; 14: 22157.
  • 21
    Uberti-Foppa C, Ferrari D, Lodini S, Reina S, Ameglio F, Grasso MA, Gallotta G, Ferrari A, Taccagni G, Lazzarin A, Lillo FB. Long-term effect of highly active antiretroviral therapy on cervical lesions in HIV-positive women. AIDS 2003; 17: 21368.
  • 22
    Monini P, Toschi E, Sgadari C, et al. The use of HAART for biological tumour therapy. J HIV Ther 2006; 11: 536.
  • 23
    Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, Mattei E, Serafino A, Cassano A, Sinibaldi-Vallebona P, Garaci E, Barone C, et al. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 2005; 24: 392331.
  • 24
    Esposito V, Palescandolo E, Spugnini EP, Montesarchio V, De LA, Cardillo I, Cortese G, Baldi A, Chirianni A. Evaluation of antitumoral properties of the protease inhibitor indinavir in a murine model of hepatocarcinoma. Clin Cancer Res 2006; 12: 26349.
  • 25
    Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, Palladino C, Leone P, Bugarini R, Malavasi L, Cafaro A, Falchi M, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 2002; 8: 22532.
  • 26
    Gaedicke S, Firat-Geier E, Constantiniu O, Lucchiari-Hartz M, Freudenberg M, Galanos C, Niedermann G. Antitumor effect of the human immunodeficiency virus protease inhibitor ritonavir: induction of tumor-cell apoptosis associated with perturbation of proteasomal proteolysis. Cancer Res 2002; 62: 69018.
  • 27
    Jiang W, Mikochik PJ, Ra JH, Lei H, Flaherty KT, Winkler JD, Spitz FR. HIV protease inhibitor nelfinavir inhibits growth of human melanoma cells by induction of cell cycle arrest. Cancer Res 2007; 67: 12217.
  • 28
    Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS, Jr., Weichold FF. Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 2002; 99: 37719.
  • 29
    Gills JJ, Lopiccolo J, Tsurutani J, Shoemaker RH, Best CJ, bu-Asab MS, Borojerdi J, Warfel NA, Gardner ER, Danish M, Hollander MC, Kawabata S, et al. Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res 2007; 13: 518394.
  • 30
    Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH. The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 2002; 62: 52305.
  • 31
    Andre P, Groettrup M, Klenerman P, de GR, Booth BL, Jr., Cerundolo V, Bonneville M, Jotereau F, Zinkernagel RM, Lotteau V. An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Natl Acad Sci USA 1998; 95: 131204.
  • 32
    Chavan S, Kodoth S, Pahwa R, Pahwa S. The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals. Blood 2001; 98: 3839.
  • 33
    Gruber A, Wheat JC, Kuhen KL, Looney DJ, Wong-Staal F. Differential effects of HIV-1 protease inhibitors on dendritic cell immunophenotype and function. J Biol Chem 2001; 276: 478403.
  • 34
    Lu W, Andrieu JM. HIV protease inhibitors restore impaired T-cell proliferative response in vivo and in vitro: a viral-suppression-independent mechanism. Blood 2000; 96: 2508.
  • 35
    Schmidtke G, Holzhutter HG, Bogyo M, Kairies N, Groll M, de GR, Emch S, Groettrup M. How an inhibitor of the HIV-I protease modulates proteasome activity. J Biol Chem 1999; 274: 3573440.
  • 36
    Sloand EM, Kumar PN, Kim S, Chaudhuri A, Weichold FF, Young NS. Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo. Blood 1999; 94: 10217.
  • 37
    Tovo PA. Highly active antiretroviral therapy inhibits cytokine production in HIV-uninfected subjects. AIDS 2000; 14: 7434.
  • 38
    Weichold FF, Bryant JL, Pati S, Barabitskaya O, Gallo RC, Reitz MS Jr. HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells. J Hum Virol 1999; 2: 2619.
  • 39
    Piccinini M, Rinaudo MT, Chiapello N, Ricotti E, Baldovino S, Mostert M, Tovo PA. The human 26S proteasome is a target of antiretroviral agents. AIDS 2002; 16: 693700.
  • 40
    Gupta AK, Cerniglia GJ, Mick R, McKenna WG, Muschel RJ. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res 2005; 65: 825665.
  • 41
    Ikezoe T, Saito T, Bandobashi K, Yang Y, Koeffler HP, Taguchi H. HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2. Mol Cancer Ther 2004; 3: 4739.
  • 42
    Srirangam A, Mitra R, Wang M, Gorski JC, Badve S, Baldridge L, Hamilton J, Kishimoto H, Hawes J, Li L, Orschell CM, Srour EF, et al. Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer. Clin Cancer Res 2006; 12: 188396.
  • 43
    Yang Y, Ikezoe T, Takeuchi T, Adachi Y, Ohtsuki Y, Takeuchi S, Koeffler HP, Taguchi H. HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling. Cancer Sci 2005; 96: 42533.
  • 44
    Gupta AK, Li B, Cerniglia GJ, Ahmed MS, Hahn SM, Maity A. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia 2007; 9: 2718.
  • 45
    Dewan MZ, Uchihara JN, Terashima K, Honda M, Sata T, Ito M, Fujii N, Uozumi K, Tsukasaki K, Tomonaga M, Kubuki Y, Okayama A, et al. Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood 2006; 107: 71624.
  • 46
    Ikezoe T, Hisatake Y, Takeuchi T, Ohtsuki Y, Yang Y, Said JW, Taguchi H, Koeffler HP. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 2004; 64: 742631.
  • 47
    Jiang Z, Pore N, Cerniglia GJ, Mick R, Georgescu MM, Bernhard EJ, Hahn SM, Gupta AK, Maity A. Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res 2007; 67: 446773.
  • 48
    Maggiorella L, Wen B, Frascogna V, Opolon P, Bourhis J, Deutsch E. Combined radiation sensitizing and anti-angiogenic effects of ionizing radiation and the protease inhibitor ritonavir in a head and neck carcinoma model. Anticancer Res 2005; 25: 435762.
  • 49
    Pore N, Gupta AK, Cerniglia GJ, Jiang Z, Bernhard EJ, Evans SM, Koch CJ, Hahn SM, Maity A. Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res 2006; 66: 92529.
  • 50
    Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004; 4: 34960.
  • 51
    Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 2008; 14: 164957.
  • 52
    Clamp AR, Jayson GC. The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br J Cancer 2005; 93: 96772.
  • 53
    Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002; 295: 238792.
  • 54
    Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006; 6: 22739.
  • 55
    Ensoli B. European Patent application, No. RM2001 A000210; Publication No.WO02/087583.
  • 56
    Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A review for clinicians. JAMA 1997; 277: 14553.
  • 57
    Angiolillo AL, Sgadari C, Sheikh N, Reaman GH, Tosato G. Regression of experimental human leukemias and solid tumors induced by Epstein-Barr virus-immortalized B cells. Leuk Lymphoma 1995; 19: 26776.
  • 58
    Sgadari C, Toschi E, Palladino C, Barillari G, Carlei D, Cereseto A, Ciccolella C, Yarchoan R, Monini P, Sturzl M, Ensoli B. Mechanism of paclitaxel activity in Kaposi's sarcoma. J Immunol 2000; 165: 50917.
  • 59
    Frederiks WM, Mook OR. Metabolic mapping of proteinase activity with emphasis on in situ zymography of gelatinases: review and protocols 1. J Histochem Cytochem 2004; 52: 71122.
  • 60
    Barillari G, Sgadari C, Fiorelli V, Samaniego F, Colombini S, Manzari V, Modesti A, Nair BC, Cafaro A, Sturzl M, Ensoli B. The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor. Blood 1999; 94: 66372.
  • 61
    Perry CM, Noble S. Saquinavir soft-gel capsule formulation. A review of its use in patients with HIV infection. Drugs 1998; 55: 46186.
  • 62
    Sadler BM, Gillotin C, Lou Y, Stein DS. In vivo effect of alpha(1)-acid glycoprotein on pharmacokinetics of amprenavir, a human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother 2001; 45: 8526.
  • 63
    Yeh KC, Deutsch PJ, Haddix H, Hesney M, Hoagland V, Ju WD, Justice SJ, Osborne B, Sterrett AT, Stone JA, Woolf E, Waldman S. Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 1998; 42: 3328.
  • 64
    Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A 1999; 96: 104038.
  • 65
    Krappmann D, Wulczyn FG, Scheidereit C. Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. EMBO J 1996; 15: 671626.
  • 66
    Horak ER, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 1992; 340: 11204.
  • 67
    Tsoli E, Zacharatos P, Siou-Plakida D, Peros J, Evangelou K, Zavras AI, Yannoukakos D, Konstantopoulou I, Asimacopoulos PJ, Kittas C, Gorgoulis VG. Growth index is independent of microvessel density in non-small-cell lung carcinomas. Hum Pathol 2002; 33: 8128.
  • 68
    Vartanian RK, Weidner N. Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am J Pathol 1994; 144: 118894.
  • 69
    Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 1992; 84: 187587.
  • 70
    Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci 2006; 11: 47991.
  • 71
    Henderson DJ, Copp AJ. Role of the extracellular matrix in neural crest cell migration. J Anat 1997; 191( Pt 4): 50715.
  • 72
    Martin P. Wound healing—aiming for perfect skin regeneration. Science 1997; 276: 7581.
  • 73
    Perris R. The extracellular matrix in neural crest-cell migration. Trends Neurosci 1997; 20: 2331.
  • 74
    Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 6714.
  • 75
    Collins LR, Ricketts WA, Yeh L, Cheresh D. Bifurcation of cell migratory and proliferative signaling by the adaptor protein Shc. J Cell Biol 1999; 147: 15618.
  • 76
    Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 2005; 1755: 3769.
  • 77
    Laurent N, de Bouard S, Guillamo JS, Christov C, Zini R, Jouault H, Andre P, Lotteau V, Peschanski M. Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Mol Cancer Ther 2004; 3: 12936.
  • 78
    Monini P, Sgadari C, Grosso MG, Bellino S, Di Biagio A, Toschi E, Bacigalupo I, Sabbatucci M, Cencioni G, Salvi E, Leone P, Ensoli B. Clinical course of classic Kaposi's sarcoma in HIV-negative patients treated with the HIV protease inhibitor indinavir. AIDS 2009; 23: 5348.