ritonavir and Leukemia--Myeloid--Acute

Topics: Antineoplastic Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Female; Humans; Hydroxychloroquine; Immune Tolerance; Infant; Leukemia, Myeloid, Acute; Lopinavir; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2

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