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 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.
Albini
A
A
National Institute for Cancer Research (IST), c/o Advanced Biotechnology Center, Largo R. Benzi 10, I-16132 Genoa, Italy. albini@vega.cba.unige.it
Morini
M
M
D'Agostini
F
F
Ferrari
N
N
Campelli
F
F
Arena
G
G
Noonan
D M
DM
Pesce
C
C
De Flora
S
S
D000111:Acetylcysteine / Q000494:pharmacology*; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000098:blood supply* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D006131:Growth Inhibitors; D019394:Ki-67 Antigen; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000111:Acetylcysteine