In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells

The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-κB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting.

[1]  J. Otte,et al.  Anticancer effects of the nitric oxide-modified saquinavir derivative saquinavir-NO against multidrug-resistant cancer cells. , 2010, Neoplasia.

[2]  M. Donia,et al.  Induction of caspase-independent apoptotic-like cell death of mouse mammary tumor TA3Ha cells in vitro and reduction of their lethality in vivo by the novel chemotherapeutic agent GIT-27NO. , 2010, Free radical biology & medicine.

[3]  J. Espinosa,et al.  Differential regulation of p53 target genes: it's (core promoter) elementary. , 2010, Genes & development.

[4]  Gen Sheng Wu.  TRAIL as a target in anti-cancer therapy. , 2009, Cancer letters.

[5]  C. Graham,et al.  Phase II study of nitric oxide donor for men with increasing prostate-specific antigen level after surgery or radiotherapy for prostate cancer. , 2009, Urology.

[6]  M. Cooperberg,et al.  Risk assessment among prostate cancer patients receiving primary androgen deprivation therapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  M. Donia,et al.  The novel NO-donating compound GIT-27NO inhibits in vivo growth of human prostate cancer cells and prevents murine immunoinflammatory hepatitis. , 2009, European journal of pharmacology.

[8]  J. McCubrey,et al.  The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt , 2009, Molecular Cancer Therapeutics.

[9]  J. Liu,et al.  The HIV protease inhibitor saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells. , 2009, Gynecologic oncology.

[10]  A. Azmi,et al.  SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status , 2009, Journal of hematology & oncology.

[11]  T. Sakai,et al.  Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1. , 2009, Nitric oxide : biology and chemistry.

[12]  Min Guan,et al.  Anti-HIV drugs for cancer therapeutics: back to the future? , 2009, The Lancet. Oncology.

[13]  B. Rigas,et al.  NO-donating NSAIDs and cancer: an overview with a note on whether NO is required for their action. , 2008, Nitric oxide : biology and chemistry.

[14]  M. Donia,et al.  Novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide (GIT-27NO) induces p53 mediated apoptosis in human A375 melanoma cells. , 2008, Nitric oxide : biology and chemistry.

[15]  F. Nicoletti,et al.  Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo , 2008, Molecular Cancer Therapeutics.

[16]  I. Tannock,et al.  Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  C. Gélinas,et al.  Regulation of programmed cell death by NF-kappaB and its role in tumorigenesis and therapy. , 2008, Advances in experimental medicine and biology.

[18]  Huating Wang,et al.  NF-κB Regulation of YY1 Inhibits Skeletal Myogenesis through Transcriptional Silencing of Myofibrillar Genes , 2007, Molecular and Cellular Biology.

[19]  J. Ferlay,et al.  Estimates of the cancer incidence and mortality in Europe in 2006. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  T. Wilt,et al.  Chemotherapy for hormone-refractory prostate cancer. , 2006, The Cochrane database of systematic reviews.

[21]  A. Doria,et al.  The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines. , 2006, Haematologica.

[22]  Rosemarie Mick,et al.  HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. , 2005, Cancer research.

[23]  S. Gibson,et al.  Transcription Factor NF-κB Differentially Regulates Death Receptor 5 Expression Involving Histone Deacetylase 1 , 2005, Molecular and Cellular Biology.

[24]  C. Tangen,et al.  Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. , 2004, The New England journal of medicine.

[25]  K. Kashfi,et al.  Nitric-oxide-donating NSAIDs as agents for cancer prevention. , 2004, Trends in molecular medicine.

[26]  P. Marrack,et al.  The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. , 2003, Immunity.

[27]  Frank Pajonk,et al.  The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. , 2002, Cancer research.

[28]  M. Falchi,et al.  HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma , 2002, Nature Medicine.

[29]  H. Nakshatri,et al.  Repression of GADD153/CHOP by NF-κB: a possible cellular defense against endoplasmic reticulum stress-induced cell death , 2001, Oncogene.

[30]  A. Belldegrun,et al.  Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) for treatment of prostate cancer: first results and review of the literature , 1999, Prostate Cancer and Prostatic Diseases.

[31]  A. Strasser,et al.  Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. , 1999, Science.

[32]  B. Gazzard,et al.  Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma. , 1999, AIDS.

[33]  C. Pellet,et al.  Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV‐related Kaposi's sarcoma , 1998, AIDS.

[34]  A. Strasser,et al.  Bim: a novel member of the Bcl‐2 family that promotes apoptosis , 1998, The EMBO journal.