Abstract

GIT-27NO (OX27NO) and Saquinavir (Saq)-NO (OX1001) are nitric oxide (NO) derivatives of the anti-inflammatory drug VGX-1027 and of the antiretroviral protease inhibitor Saq. We have presently studied the chemotherapeutic potential of these derivatives in the 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, oxygen and nitrogen species was also determined. The efficacy of the compounds was evaluated in vivo in BALB/c mice injected with CT26CL25. 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 as 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, co-treatment with 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 pro-apoptotic signals followed by caspase-dependent apoptosis. In contrast, Saq-NO blocked cell proliferation and changed 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 resulting in cell death.