The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Abstract

PurposeRefractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.Materials and methodsA comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.ResultsSeveral of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1–24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).ConclusionHere, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

Acute lymphoblastic leukemia onset in a 3‐year‐old child with COVID‐19

“…Additional evidence supports the potential use of human immunodeficiency virus protease inhibitors (HIV‐PI; eg, lopinavir) as antineoplastic drugs 12 . Furthermore, the preclinical study of Meier‐Stephenson et al 13 focused on the identification of HIV‐PI‐mediated cytotoxicity in pediatric leukemia cells.…”

The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

“…Tian et al also reported phosphorylation of eIF2α and increased protein levels of ATF4 and CHOP in response to nelfinavir in glioblastoma cells [ 52 ]. Phosphorylation of eIF2α was also reported in nelfinavir-treated pediatric refractory leukemia cells [ 44 ]. In renal cancer cells, ER stress was shown to be induced by nelfinavir, as evidenced by the increase in GRP78, endoplasmic reticulum resident protein 44 (ERp44), and endoplasmic oxidoreductin-1-like protein α (ERO1-Lα) [ 28 ].…”

“…Davis and colleagues reported cleavage of caspase-7 in nelfinavir-treated cisplatin-sensitive and -resistant cervical cancer cells, which corroborated similar findings in breast cancer cells [ 42 , 43 ]. In pediatric leukemia cells treated with nelfinavir, PARP cleavage was associated with the cleavage of upstream apoptosis initiator caspase-9 [ 44 ]. Liu et al observed a resensitization of doxorubicin-resistant chronic myeloid leukemia (CML) cells during co-treatment of suboptimal doses of nelfinavir with doxorubicin, which resulted in increased apoptosis associated to caspase-3 cleavage, increased proapoptotic protein Bax, and decreased anti-apoptotic protein Bcl-2 [ 45 ].…”

“…The authors linked ER stress as an upstream activating factor of autophagy and concluded that the induced autophagy could be a compensatory survival mechanism, as the inhibition of autophagy by 3-MA resulted in enhanced cytotoxicity [ 19 ]. Enhanced apoptosis due to combined treatment of nelfinavir and 3-MA was also observed in refractory pediatric leukemia cells [ 44 ]. Gill et al later highlighted four possible mechanisms by which nelfinavir could exert its autophagy-inducing properties.…”

Investigation of Cytostatic Activity of the Methenamine Silver in Vitro and in Vivo

“…Designing of novel cytostatic agents for leucosis treatment is a challenging task for modern pharmacology and medicine. Especially acute problem is a resistant form of decease [1][2]. A lot of modern approaches are used now for development delivery systems and screening of novel agents, e. g. virtual ligand screening [3][4].…”