The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

Maksimović‐Ivanić, Danijela; Mijatović, Sanja; Miljković, Djordje; Harhaji-Trajković, Ljubica; Timotijević, Gordana; Mojić, Marija; Dabideen, Darrin; Cheng, Kai; McCubrey, James A.; Mangano, Katia; Al‐Abed, Yousef; Libra, Massimo; Garotta, Gianni; Stošić‐Grujičić, Stanislava; Nicoletti, Ferdinando

doi:10.1158/1535-7163.mct-08-0998

Cited by 39 publications

(59 citation statements)

References 39 publications

(51 reference statements)

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“…1), with enhanced anticancer properties and reduced toxicity. In particular, Saq-NO inhibited at significantly lower IC 50 values compared to the parental compound the in vitro growth of rodent and human melanoma cell lines B16 and A375 (9,10) showing potent anticancer effects also against multidrug-resistant cancer cells (11). Neither p53 mutation nor depletion nor expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), or breast cancer resistance protein 1 (BRCP1) affected the anticancer activity of Saq-NO or Saq.…”

Section: Introductionmentioning

confidence: 92%

“…In vitro studies on the B16 and A375 melanoma cell lines Saq-NO have shown a cell-dependent pharmacological profile of Saq-NO. While Saq-NO efficiently exerted Akt-independent cytostatic effects promoting terminal differentiation into Schwann-like cells in B16 cells (9), it exerted a strong cytotoxic effect on the inducible nitric oxide synthase (iNOS) positive A375 cells (10). In these cells, Saq-NO-triggered apoptosis was dependent on transient Akt up-regulation and reduced pERK and iNOS expression that were observed within the first 12 hours of exposure to the drug (10).…”

Section: Introductionmentioning

confidence: 99%

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Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Donia¹,

Mangano²,

Fagone³

et al. 2012

Oncology Reports

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Abstract.We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in vitro and in vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in vitro as well as in vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in vivo growth of xenotransplants.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Donia¹,

Mangano²,

Fagone³

et al. 2012

Oncology Reports

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“…Unfortunately, the presence of side effects seriously limited Saq usage and presented the opportunity for designing different forms of this drug with an advanced pharmacological profile (13). Attachment of the nitric oxide (NO) moiety to saquinavir generated a new drug with significantly improved antitumor characteristics (14). Saq-NO was completely nontoxic in vitro and in vivo, while its activity against a wide range of cell lines was qualitatively and quantitatively increased in comparison to the parental drug (14).…”

Section: Introductionmentioning

confidence: 99%

No-Modified Saquinavir is Equally Efficient Against Doxorubicin Sensitive and Resistant Non-Small Cell Lung Carcinoma Cells / MODIFIKOVANA KOVANA FORMA SAKVINAVIRA EFIKASNO SU PRIMI RA RAST ĆELIJA NESITNOĆELIJSKOG KARCINOMA PLUĆA RAZLIČITE OSETUIVOSTI NA DOKSORUBICIN

Mijatović¹,

Pešić²,

Mojić³

et al. 2013

Journal of Medical Biochemistry

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SummaryBackground: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of cancer cell lines in vitro and in vivo more potently than the original compound in a nontoxic fashion. In addition, chemoand immunosensitizing properties were observed. The aim of the present study was to evaluate its anticancer action against non-small cell lung carcinoma cells in their doxorubicin (DOXO) sensitive and resistant phenotype (NCI-H460 and NCI-H460/R). Methods: The viability of cells was analyzed by MTT and crystal violet assays. DR5 expression was estimated by real time RT-PCR and flow cytometry. Activity of P-glycoprotein (P-gp) pumps was evaluated by the Rho123 accumulation assay. Results: Saq-NO diminished the viability of lung cancer cells through induction of cell cycle arrest in the G 0 /G 1 phase independently of the overexpression of the P-gp pumps. In addition, Saq-NO elevated or completely reconstituted the doxorubicin efficacy in NCI-H460 and NCI-H460/R, respecti vely. The chemosensitizing effect in DOXO resistant cells was a consequence of P-gp inhibition which was found to be

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“…Previous work carried out by ourselves and others has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect acquires antitumoural [11][12][13][14][15][16][17] and immunomodulatory [12,18,19] properties along with reduced toxicity in vitro and in vivo [12].…”

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confidence: 99%

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Fagone

Mangano

Quattrocchi

et al. 2015

Basic Clin Pharmacol Toxicol

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HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non-steroidal, anti-inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect, acquires antitumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO-hybridization on two other PIs, Lopinavir and Ritonavir. The two NO-derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir-NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir-NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir-NO effects overlapped those of Ritonavir. These data demonstrate that NO-hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T-cell secretory capacity. Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis. Antiretroviral protease inhibitors (PIs) in combination with nucleoside or non-nucleoside reverse transcriptase inhibitors are the basis for the highly active antiretroviral therapy (HA-ART) that is efficient in suppression of HIV replication and reduction of clinical manifestations of the disease [1].In addition to their primary pharmacological indication, these drugs have also been described to possess antineoplastic and immunomodulatory properties both in in vitro and in vivo pre-clinical settings [2][3][4].However, serious side effects including dyslipidaemia, insulin resistance, lipodystrophy, hepatotoxicity and atherosclerotic cardiovascular complications [5][6][7][8][9] have dampened the possible extension of these drugs to therapeutic areas different than HIV infection.It has been previously demonstrated that nitric oxide (NO)-hybridization may reduce toxicity of parental compounds while enhancing the pharmacological potency of the drugs [10]. Along this line of research, several derivatives of PIs have been synthesized at OncoNOx (Copenhagen, Denmark) by covalent attachment of NO moiety to the parental molecules.Previous work carried out by ourselves and others has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretro...

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The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

Cited by 39 publications

References 39 publications

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

No-Modified Saquinavir is Equally Efficient Against Doxorubicin Sensitive and Resistant Non-Small Cell Lung Carcinoma Cells / MODIFIKOVANA KOVANA FORMA SAKVINAVIRA EFIKASNO SU PRIMI RA RAST ĆELIJA NESITNOĆELIJSKOG KARCINOMA PLUĆA RAZLIČITE OSETUIVOSTI NA DOKSORUBICIN

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

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