Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Donia,Marco; Mangano,Katia; Fagone,Paolo; De Pasquale,Rocco; Dinotta,Franco; Coco,Marinella; Padron,Julio; Al-Abed,Yousef; Giovanni Lombardo,Giuseppe  Angelo; Maksimovic-Ivanic,Danijela; Mijatovic,Sanja; Zocca,Mai-Britt; Perciavalle,Vincenzo; Stosic-Grujicic,Stanislava; Nicoletti,Ferdinando

doi:10.3892/or.2012.1840

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Authors:
- Marco Donia
- Katia Mangano
- Paolo Fagone
- Rocco De Pasquale
- Franco Dinotta
- Marinella Coco
- Julio Padron
- Yousef Al-Abed
- Giuseppe Angelo Giovanni Lombardo
- Danijela Maksimovic-Ivanic
- Sanja Mijatovic
- Mai-Britt Zocca
- Vincenzo Perciavalle
- Stanislava Stosic-Grujicic
- Ferdinando Nicoletti
View Affiliations

Affiliations: Department of Bio-Medical Sciences, University of Catania, Catania, Italy, Department of Dermatology Clinic, University of Catania, Catania, Italy, NicOx Research Institute, Bresso, Milan, Italy, Feinsten Institute for Medical Research, Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Manhasset, NY, USA, Department of Plastic and Reconstructive Surgery, Cannizzaro Hospital, University of Catania, Catania, Italy, Department of Immunology, Institute for Biological Research ‘Sinisa Stankovic’, Belgrade University, Belgrade, Serbia, Onconox Aps, Copenhagen, Denmark
Published online on: May 29, 2012 https://doi.org/10.3892/or.2012.1840
Pages: 682-688

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in vitro and in vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in vitro as well as in vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in vivo growth of xenotransplants.

View Figures

View References

1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
2	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar
3	Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010. View Article : Google Scholar
4	Bedikian AY, Johnson MM, Warneke CL, et al: Does complete response to systemic therapy in patients with stage IV melanoma translate into long-term survival? Melanoma Res. 21:84–90. 2011. View Article : Google Scholar : PubMed/NCBI
5	Petrella T, Quirt I, Verma S, Haynes AE, Charette M and Bak K; Members of the Melanoma Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care. Single-agent interleukin-2 in the treatment of metastatic melanoma. Curr Oncol. 14:21–26. 2007. View Article : Google Scholar
6	Garbe C, Eigentler TK, Keilholz U, Hauschild A and Kirkwood JM: Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 16:5–24. 2011. View Article : Google Scholar : PubMed/NCBI
7	Andersen MH, Junker N, Ellebaek E, Svane IM and Thor Straten P: Therapeutic cancer vaccines in combination with conventional therapy. J Biomed Biotechnol. 2010:2376232010. View Article : Google Scholar : PubMed/NCBI
8	Hershkovitz L, Schachter J, Treves AJ and Besser MJ: Focus on adoptive T cell transfer trials in melanoma. Clin Dev Immunol. 2010:2602672010. View Article : Google Scholar : PubMed/NCBI
9	Maksimovic-Ivanic D, Mijatovic S, Miljkovic D, et al: The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt. Mol Cancer Ther. 8:1169–1178. 2009. View Article : Google Scholar : PubMed/NCBI
10	Mijatovic S, Maksimovic-Ivanic D, Mojic M, et al: Cytotoxic and immune-sensitizing properties of nitric oxide-modified saquinavir in iNOS-positive human melanoma cells. J Cell Physiol. 226:1803–1812. 2010. View Article : Google Scholar : PubMed/NCBI
11	Rothweiler F, Michaelis M, Brauer P, et al: Anticancer effects of the nitric oxide-modified saquinavir derivative saquinavir-NO against multidrug-resistant cancer cells. Neoplasia. 12:1023–1030. 2010.
12	Donia M, Maksimovic-Ivanic D, Mijatovic S, Mojic M, Miljkovic D, Timotijevic G, Fagone P, Caponnetto S, Al-Abed Y, McCubrey J, Stosic-Grujicic S and Nicoletti F: 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. Cell Cycle. 10:492–499. 2011. View Article : Google Scholar
13	Tang CH and Grimm EA: Depletion of endogenous nitric oxide enhances cisplatin-induced apoptosis in a p53-dependent manner in melanoma cell lines. J Biol Chem. 279:288–298. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ekmekcioglu S, Ellerhorst J, Smid CM, et al: Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res. 6:4768–4775. 2000.PubMed/NCBI
15	Ekmekcioglu S, Ellerhorst JA and Prieto VG: Tumor iNOS predicts poor survival for stage III melanoma patients. Int J Cancer. 119:861–866. 2006. View Article : Google Scholar : PubMed/NCBI
16	Johansson CC, Egyházi S, Masucci G, et al: Prognostic significance of tumor iNOS and COX-2 in stage III malignant cutaneous melanoma. Cancer Immunol Immunother. 58:1085–1094. 2009. View Article : Google Scholar : PubMed/NCBI
17	Yang Z, Yang S, Misner BJ, Chiu R, Liu F and Meyskens FL Jr: Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol. Mol Cancer Ther. 7:3751–3760. 2008. View Article : Google Scholar
18	White N, Knight GE, Butler PE and Burnstock G: An in vivo model of melanoma: treatment with ATP. Purinergic Signal. 5:327–333. 2009.PubMed/NCBI
19	Huerta S, Chilka S and Bonavida B: Nitric oxide donors: novel cancer therapeutics (Review). Int J Oncol. 33:909–927. 2008.PubMed/NCBI
20	Hickok JR and Thomas DD: Nitric oxide and cancer therapy: the emperor has NO clothes. Curr Pharm Des. 16:381–391. 2010. View Article : Google Scholar : PubMed/NCBI
21	Hirst D and Robson T: Nitric oxide in cancer therapeutics: interaction with cytotoxic chemotherapy. Curr Pharm Des. 16:411–420. 2010. View Article : Google Scholar : PubMed/NCBI
22	Chin MP and Deen WM: Prediction of nitric oxide concentrations in melanomas. Nitric Oxide. 23:319–326. 2010. View Article : Google Scholar : PubMed/NCBI
23	Nanni S, Benvenuti V, Grasselli A, et al: Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest. 119:1093–1108. 2009. View Article : Google Scholar : PubMed/NCBI
24	Glynn SA, Boersma BJ, Dorsey TH, et al: Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J Clin Invest. 120:3843–3854. 2010. View Article : Google Scholar : PubMed/NCBI
25	Ambs S and Glynn SA: Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer. Cell Cycle. 10:619–624. 2011. View Article : Google Scholar : PubMed/NCBI
26	McMurtry V, Saavedra JE, Nieves-Alicea R, Simeone AM, Keefer LK and Tari AM: JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells. Int J Oncol. 38:963–971. 2011.
27	Sikora AG, Gelbard A, Davies MA, et al: Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy. Clin Cancer Res. 16:1834–1844. 2010. View Article : Google Scholar : PubMed/NCBI