saquinavir and Leukemia--Myeloid--Acute

Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enzyme Activation; HIV Protease Inhibitors; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia, Myeloid, Acute; Nitric Oxide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ribosomal Protein S6 Kinases, 70-kDa; Saquinavir

Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML.. We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro.. Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the β2 proteasome activity that is not targeted by bortezomib/carfilzomib.. Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.

Topics: Apoptosis; Cytotoxins; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Leukemic; HIV Protease Inhibitors; Humans; Leukemia, Myeloid, Acute; Lopinavir; Nelfinavir; Phosphorylation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proto-Oncogene Proteins c-akt; Ritonavir; Saquinavir; Signal Transduction; Tumor Cells, Cultured