The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt
Само за регистроване кориснике
2009
Аутори
Maksimović-Ivanić, DanijelaMijatović, Sanja
Miljković, Djordje
Harhaji-Trajković, Ljubica
Timotijević, Gordana
Mojić, Marija
Dabideen, Darrin
Cheng, Kai Fan
McCubrey, James A.
Mangano, Katia
Al-Abed, Yousef
Libra, Massimo
Garotta, Gianni
Stošić-Grujičić, Stanislava
Nicoletti, Ferdinando
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 1316 cells, up-regulated p53 expression, and promoted the differentiation of these two cell types into oligodendrocytes or Schwann-like cells, respectively. Although it has bee...n 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. [Mol Cancer Ther 2009;8(5):1169-78]
Извор:
Molecular Cancer Therapeutics, 2009, 8, 5, 1169-1178Издавач:
- Amer Assoc Cancer Research, Philadelphia
Финансирање / пројекти:
- Физиолошка и фармаколошка модулација имуноинфламаторних и малигних болести (RS-MESTD-MPN2006-2010-143029)
- University of Catania
DOI: 10.1158/1535-7163.MCT-08-0998
ISSN: 1535-7163
PubMed: 19417156
WoS: 000266189900021
Scopus: 2-s2.0-66849109073
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Maksimović-Ivanić, Danijela AU - Mijatović, Sanja AU - Miljković, Djordje AU - Harhaji-Trajković, Ljubica AU - Timotijević, Gordana AU - Mojić, Marija AU - Dabideen, Darrin AU - Cheng, Kai Fan AU - McCubrey, James A. AU - Mangano, Katia AU - Al-Abed, Yousef AU - Libra, Massimo AU - Garotta, Gianni AU - Stošić-Grujičić, Stanislava AU - Nicoletti, Ferdinando PY - 2009 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/357 AB - 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 1316 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. [Mol Cancer Ther 2009;8(5):1169-78] PB - Amer Assoc Cancer Research, Philadelphia T2 - Molecular Cancer Therapeutics T1 - The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt EP - 1178 IS - 5 SP - 1169 VL - 8 DO - 10.1158/1535-7163.MCT-08-0998 ER -
@article{ author = "Maksimović-Ivanić, Danijela and Mijatović, Sanja and Miljković, Djordje and Harhaji-Trajković, Ljubica and Timotijević, Gordana and Mojić, Marija and Dabideen, Darrin and Cheng, Kai Fan and McCubrey, James A. and Mangano, Katia and Al-Abed, Yousef and Libra, Massimo and Garotta, Gianni and Stošić-Grujičić, Stanislava and Nicoletti, Ferdinando", year = "2009", abstract = "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 1316 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. [Mol Cancer Ther 2009;8(5):1169-78]", publisher = "Amer Assoc Cancer Research, Philadelphia", journal = "Molecular Cancer Therapeutics", title = "The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt", pages = "1178-1169", number = "5", volume = "8", doi = "10.1158/1535-7163.MCT-08-0998" }
Maksimović-Ivanić, D., Mijatović, S., Miljković, D., Harhaji-Trajković, L., Timotijević, G., Mojić, M., Dabideen, D., Cheng, K. F., McCubrey, J. A., Mangano, K., Al-Abed, Y., Libra, M., Garotta, G., Stošić-Grujičić, S.,& Nicoletti, F.. (2009). The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt. in Molecular Cancer Therapeutics Amer Assoc Cancer Research, Philadelphia., 8(5), 1169-1178. https://doi.org/10.1158/1535-7163.MCT-08-0998
Maksimović-Ivanić D, Mijatović S, Miljković D, Harhaji-Trajković L, Timotijević G, Mojić M, Dabideen D, Cheng KF, McCubrey JA, Mangano K, Al-Abed Y, Libra M, Garotta G, Stošić-Grujičić S, Nicoletti F. The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt. in Molecular Cancer Therapeutics. 2009;8(5):1169-1178. doi:10.1158/1535-7163.MCT-08-0998 .
Maksimović-Ivanić, Danijela, Mijatović, Sanja, Miljković, Djordje, Harhaji-Trajković, Ljubica, Timotijević, Gordana, Mojić, Marija, Dabideen, Darrin, Cheng, Kai Fan, McCubrey, James A., Mangano, Katia, Al-Abed, Yousef, Libra, Massimo, Garotta, Gianni, Stošić-Grujičić, Stanislava, Nicoletti, Ferdinando, "The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt" in Molecular Cancer Therapeutics, 8, no. 5 (2009):1169-1178, https://doi.org/10.1158/1535-7163.MCT-08-0998 . .