Anticancer and Differentiation Properties of the Nitric Oxide Derivative of Lopinavir in Human Glioblastoma Cells

Abstract

Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of its NO-derivative Lopinavir-NO (Lopi-NO) on the in vitro growth of LN-229 and U-251 human GBM cell lines. Lopi-NO reduced the viability of LN-229 and U-251 cells at significantly lower concentrations than the parental drug. In particular, Lopi-NO inhibited tumor cell proliferation and induced the differentiation of U-251 cells toward an astrocyte-like phenotype without triggering significant cell death in both cell types. The anticancer effect of Lopi-NO was persistent even upon drug removal. Furthermore, Lopi-NO induced strong autophagy that did not appear to be related to its chemotherapeutic action. Overall, our results suggest that Lopi-NO could be a potential effective anticancer drug for GBM treatment.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer′s Disease: Conventionally Pathogenetic or Unconventionally Protective?

“…It is also worth noting that the biological function of MIF can be inhibited by nitrosylation [72], and hence nitric oxide (NO) donors may indirectly promote MIF inhibition. Along these lines, we propose that together with NO-NSAID, that have been proven effective in both preclinical and clinical settings [73,74], and also other NO-donors such as the recently characterized lopinavir-NO and ritonavir-NO [75][76][77][78], deserve consideration as drugs to be used in the treatment of AD patients. These drugs NO donors could combine beneficial anti-inflammatory properties along with beneficial effects of NO on vascular conditions associated with AD.…”

Impaired Expression of Tetraspanin 32 (TSPAN32) in Memory T Cells of Patients with Multiple Sclerosis

“…We also studied the possible diagnostic and prognostic value of TSPAN32 expression in PBMC of MS patients, on the course of the disease. The use of whole-genome expression databases has been largely exploited [25][26][27][28] for the characterization of pathogenic pathways and to identify therapeutic targets for a variety of disorders, including immunoinflammatory and autoimmune diseases [29][30][31][32][33][34][35][36], cancer [37][38][39], and has allowed dismantling pathogenetic pathways [40][41][42], along with the identification of novel tailored therapeutic targets [43][44][45][46].…”

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

“…Moreover, it has been found that nitrosylation could dampen MIF activity [108]. Hence, another possible interesting approach may be to use nitric oxide (NO)-hybridized drugs, such as NO-aspirin or NO-hybridized antiretroviral protease inhibitors, including lopinavir-NO [87,92,94,95] and ritonavir-NO [87,93], for the treatment of NB and eventually other diseases in which MIF is involved.…”

“…DNA microarray analysis is a widely used technique that helps to identify diagnostic tools, pathogenetic pathways, and novel cellular and pharmacological therapeutic targets in several types of pathologies including immunoinflammatory and autoimmune diseases [85][86][87][88][89][90], neurodegenerative diseases [91], and cancer [92][93][94][95] and allows identification of potential cellular and molecular therapeutic targets [96,97].…”