The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt.
Application of the HIV protease inhibitor saquinavir (Saq) to cancer chemotherapy is limited by its numerous side effects. To overcome this toxicity, we modified the original compound by covalently attaching a nitric oxide (NO) group. We compared the efficacy of the parental and NO-modified drugs in vitro and in vivo. The novel compound saquinavir-NO (Saq-NO) significantly reduced the viability of a wide spectrum of human and rodent tumor cell lines at significantly lower concentration than the unmodified drug. In contrast to Saq, Saq-NO had no effect on the viability of primary cells and drastically reduced B16 melanoma growth in syngeneic C57BL/6 mice. In addition, at the equivalent of the 100% lethal dose of Saq, Saq-NO treatment caused no apparent signs of toxicity. Saq-NO blocked the proliferation of C6 and B16 cells, up-regulated p53 expression, and promoted the differentiation of these two cell types into oligodendrocytes or Schwann-like cells, respectively. Although it has been well documented that Saq decreases tumor cell viability by inhibiting Akt, the anticancer properties of Saq-NO were completely independent of the phosphatidylinositol 3-kinase/Akt signaling pathway. Moreover, Saq-NO transiently up-regulated Akt phosphorylation, delivering a protective signal that could be relevant for primary cell protection and the absence of drug toxicity in vivo. It was unlikely that released NO was independently responsible for these drug effects because Saq-NO treatment increased intracellular and secreted NO levels only slightly. Rather, the chemical modification seems to have produced a qualitatively new chemical entity, which may have a unique mode of action against cancer cells.
Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade University, Catania, Italy.
Danijela
D
Maksimovic-Ivanic
Sanja
S
Mijatovic
Djordje
D
Miljkovic
Ljubica
L
Harhaji-Trajkovic
Gordana
G
Timotijevic
Marija
M
Mojic
Darrin
D
Dabideen
Kai Fan
KF
Cheng
James A
JA
McCubrey
Katia
K
Mangano
Yousef
Y
Al-Abed
Massimo
M
Libra
Gianni
G
Garotta
Stanislava
S
Stosic-Grujicic
Ferdinando
F
Nicoletti
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D019258:Saquinavir / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D009569:Nitric Oxide; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D019258:Saquinavir