280 HIV protease inhibitor ritonavir increases heat sensitivity of renal cancer cells by inhibiting heat-induced NF-kappaB activation

AbstractProteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers.Abstract Figure

Download Full-text

The HIV protease inhibitor saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells

Gynecologic Oncology ◽

10.1016/j.ygyno.2008.11.028 ◽

2009 ◽

Vol 112 (3) ◽

pp. 623-630 ◽

Cited By ~ 32

Author(s):

Karen McLean ◽

Natalie A. VanDeVen ◽

Dorothy R. Sorenson ◽

Sayeema Daudi ◽

J. Rebecca Liu

Keyword(s):

Ovarian Cancer ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Protease Inhibitor ◽

Cancer Cells ◽

Hiv Protease ◽

Ovarian Cancer Cells ◽

Hiv Protease Inhibitor

Download Full-text

Altered Myocellular and Abdominal Fat Partitioning Predict Disturbance in Insulin Action in HIV Protease Inhibitor-Related Lipodystrophy

Diabetes ◽

10.2337/diabetes.51.11.3163 ◽

2002 ◽

Vol 51 (11) ◽

pp. 3163-3169 ◽

Cited By ~ 96

Author(s):

S. K. Gan ◽

K. Samaras ◽

C. H. Thompson ◽

E. W. Kraegen ◽

A. Carr ◽

...

Keyword(s):

Protease Inhibitor ◽

Insulin Action ◽

Abdominal Fat ◽

Hiv Protease ◽

Hiv Protease Inhibitor

Download Full-text

Identification of the Differentially Expressed Genes Involved in the Synergistic Neurotoxicity of an HIV Protease Inhibitor and Methamphetamine

Current HIV Research ◽

10.2174/1570162x17666190924200354 ◽

2019 ◽

Vol 17 (4) ◽

pp. 290-303

Author(s):

Sangsang Li ◽

Yanfei Li ◽

Bingpeng Deng ◽

Jie Yan ◽

Yong Wang

Keyword(s):

Protease Inhibitor ◽

Growth Inhibition ◽

Quantitative Polymerase Chain Reaction ◽

Differentially Expressed Gene ◽

Antiretroviral Drugs ◽

Differentially Expressed ◽

Hiv Protease ◽

Hiv Protease Inhibitor ◽

Dopaminergic Cells ◽

Immunodeficiency Syndrome

Background: The abuse of psychostimulants such as methamphetamine (METH) is common in human immunodeficiency virus (HIV)-infected individuals. Acquired immunodeficiency syndrome (AIDS) patients taking METH and antiretroviral drugs could suffer severe neurologic damage and cognitive impairment. Objective: To reveal the underlying neuropathologic mechanisms of an HIV protease inhibitor (PI) combined with METH, growth-inhibition tests of dopaminergic cells and RNA sequencing were performed. Methods: A combination of METH and PI caused more growth inhibition of dopaminergic cells than METH alone or a PI alone. Furthermore, we identified differentially expressed gene (DEG) patterns in the METH vs. untreated cells (1161 genes), PI vs. untreated cells (16 genes), METH-PI vs. PI (3959 genes), and METH-PI vs. METH groups (14 genes). Results: The DEGs in the METH-PI co-treatment group were verified in the brains of a mouse model using quantitative polymerase chain reaction and were involved mostly in the regulatory functions of cell proliferation and inflammation. Conclusion: Such identification of key regulatory genes could facilitate the study of their neuroprotective potential in the users of METH and PIs.

Download Full-text