Therapeutic potential of nitric oxide-modified drugs in colon cancer cells.
We have examined the influence of the nitric oxide (NO)-modified anti-inflammatory drug (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) named GIT-27NO or the NO-modified antiviral drug saquinavir (Saq) named Saq-NO on two colon cancer cell lines, mouse CT26CL25 and human HCT116. The effects of the drugs on cell viability, apoptosis, proliferation, and metastatic potential were analyzed. The release of NO and oxygen and nitrogen species was also determined. The efficacy of the drugs was evaluated in vivo in BALB/c mice injected with CT26CL25 cells. Both agents suppressed the growth of colon cancer cells in vitro and reduced tumor volume in syngeneic BALB/c mice. However, their mechanisms of action were different because GIT-27NO released larger amounts of nitrite than Saq-NO in cell cultures and its antitumor action depended on the intracellular NO release inside the cells. On the contrary, Saq-NO released barely detectable amounts of NO and its antitumor action was NO-independent. In fact, cotreatment with an NO-peroxynitrite scavenger revealed that GIT-27NO but not Saq-NO acts through peroxynitrite-mediated cell destruction. At the cellular level, GIT-27NO prevalently induced proapoptotic signals followed by caspase-dependent apoptosis. In contrast, Saq-NO blocked cell proliferation, changed the adhesive, migratory, and invasive properties of the cells, and decreased metastatic potential in vivo. In conclusion, differences in NO release and oxidative stress generation between GIT-27NO and Saq-NO resulted in different mechanisms that caused cell death.
Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
Marija
M
Mojic
Sanja
S
Mijatovic
Danijela
D
Maksimovic-Ivanic
Djordje
D
Miljkovic
Stanislava
S
Stosic-Grujicic
Marija
M
Stankovic
Katia
K
Mangano
Salvatore
S
Travali
Marco
M
Donia
Paolo
P
Fagone
Mai-Britt
MB
Zocca
Yousef
Y
Al-Abed
James A
JA
McCubrey
Ferdinando
F
Nicoletti
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000737:chemistry* / Q000502:physiology; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019258:Saquinavir / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C518641:3-phenyl-4,5-dihydro-5-isoxazole acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D010080:Oxazoles; D009569:Nitric Oxide; D020169:Caspases; D019258:Saquinavir