This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Albini, A. Articles by De Flora, S. Search for Related Content PubMed PubMed Citation Articles by Albini, A. Articles by De Flora, S.

Inhibition of Angiogenesis-driven Kaposi’s Sarcoma Tumor Growth in Nude Mice by Oral N-Acetylcysteine¹

National Institute for Cancer Research (IST), I-16132 Genoa, Italy [A. A., M. M., N. F., F. C., G. A., D. M. N.], and Departments of Health Sciences [F. D., S. D. F.] and Biophysical, Medical and Dental Sciences [C. P.], University of Genoa, I-16132 Genoa, Italy

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi’s sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi’s sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.

This article has been cited by other articles:

				Q. Ma, L. E. Cavallin, B. Yan, S. Zhu, E. M. Duran, H. Wang, L. P. Hale, C. Dong, E. Cesarman, E. A. Mesri, et al. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma PNAS, May 26, 2009; 106(21): 8683 - 8688. [Abstract] [Full Text] [PDF]

				N. Vannini, G. Lorusso, R. Cammarota, M. Barberis, D. M. Noonan, M. B. Sporn, and A. Albini The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent Mol. Cancer Ther., December 1, 2007; 6(12): 3139 - 3146. [Abstract] [Full Text] [PDF]

				T. Abruzzo, T. Tun, and A. Sambanis Efficient Transmicrocatheter Delivery of Functional Fibroblasts with a Bioengineered Collagen Gel-Platinum Microcoil Complex: Toward the Development of Endovascular Cell Therapy for Cerebral Aneurysms AJNR Am. J. Neuroradiol., September 1, 2007; 28(8): 1586 - 1593. [Abstract] [Full Text] [PDF]

				P. Larghero, R. Vene, S. Minghelli, G. Travaini, M. Morini, N. Ferrari, U. Pfeffer, D. M. Noonan, A. Albini, and R. Benelli Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression Carcinogenesis, May 1, 2007; 28(5): 1008 - 1020. [Abstract] [Full Text] [PDF]

				R. Reliene and R. H. Schiestl Antioxidants Suppress Lymphoma and Increase Longevity in Atm-Deficient Mice J. Nutr., January 1, 2007; 137(1): 229S - 232S. [Abstract] [Full Text] [PDF]

				A. Albini and D. M. Noonan Rescuing COX-2 Inhibitors From the Waste Bin J Natl Cancer Inst, June 1, 2005; 97(11): 859 - 860. [Full Text] [PDF]

				G. M. Gordillo, D. Onat, M. Stockinger, S. Roy, M. Atalay, F. M. Beck, and C. K. Sen A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation Am J Physiol Cell Physiol, October 1, 2004; 287(4): C866 - C873. [Abstract] [Full Text] [PDF]

				G. Fassina, R. Vene, M. Morini, S. Minghelli, R. Benelli, D. M. Noonan, and A. Albini Mechanisms of Inhibition of Tumor Angiogenesis and Vascular Tumor Growth by Epigallocatechin-3-Gallate Clin. Cancer Res., July 15, 2004; 10(14): 4865 - 4873. [Abstract] [Full Text] [PDF]

				A. Agarwal, U. Munoz-Najar, U. Klueh, S.-C. Shih, and K. P. Claffey N-Acetyl-Cysteine Promotes Angiostatin Production and Vascular Collapse in an Orthotopic Model of Breast Cancer Am. J. Pathol., May 1, 2004; 164(5): 1683 - 1696. [Abstract] [Full Text] [PDF]

				W. Gu, D. Weihrauch, K. Tanaka, J. P. Tessmer, P. S. Pagel, J. R. Kersten, W. M. Chilian, and D. C. Warltier Reactive oxygen species are critical mediators of coronary collateral development in a canine model Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1582 - H1589. [Abstract] [Full Text] [PDF]

				K. R. Sekhar, P. A. Crooks, V. N. Sonar, D. B. Friedman, J. Y. Chan, M. J. Meredith, J. H. Starnes, K. R. Kelton, S. R. Summar, S. Sasi, et al. NADPH Oxidase Activity Is Essential for Keap1/Nrf2-mediated Induction of GCLC in Response to 2-Indol-3-yl-methylenequinuclidin-3-ols Cancer Res., September 1, 2003; 63(17): 5636 - 5645. [Abstract] [Full Text] [PDF]

				L. A. Dourmishev, A. L. Dourmishev, D. Palmeri, R. A. Schwartz, and D. M. Lukac Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis Microbiol. Mol. Biol. Rev., June 1, 2003; 67(2): 175 - 212. [Abstract] [Full Text] [PDF]

				J. Stebbing, S. Portsmouth, and B. Gazzard How does HAART lead to the resolution of Kaposi's sarcoma? J. Antimicrob. Chemother., May 1, 2003; 51(5): 1095 - 1098. [Full Text] [PDF]

				U. Pfeffer, D. Bisacchi, M. Morini, R. Benelli, S. Minghelli, A. Vacca, D. M. Noonan, and A. Albini Human Chorionic Gonadotropin Inhibits Kaposi's Sarcoma Associated Angiogenesis, Matrix Metalloprotease Activity, and Tumor Growth Endocrinology, August 1, 2002; 143(8): 3114 - 3121. [Abstract] [Full Text] [PDF]