Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced g lutathione, has cancer chemopreventive properties attributable to its nucle ophilicity, antioxidant activity, and a variety of other mechanisms. We dem onstrated recently that NAC has anti-invasive, antimetastatic, and antiangi ogenic 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 da ily administration of NAC with drinking water, initiated after the tumor ma ss had become established and detectable, produced a sharp inhibition of tu mor growth, with regression of tumors in half of the treated mice along wit h a markedly prolonged median survival time. The production of vascular end othelial growth factor (VEGF) and certain proliferation markers (proliferat ing cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sa rcomas from NAC-treated mice than from control mice. Treatment of KS-Imm ce lls 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 si gnificantly inhibited VEGF production but did not affect proliferation mark ers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mm NAC. Taken together, these findings provide evi dence 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 act ion, has a strong antiangiogenic potential that could be exploited for prev enting cancer progression as well as used in cancer adjuvant therapy.