Abstract
Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.
Highlights
The results suggest a certain activation of the IRE1a branch, given the increased protein expression of both IRE1a and sXBP1, which was more evident with RDD-19 (Figure 6)
The introduction of highly active antiretroviral therapy (HAART) significantly decreased the incidence of several forms of cancer, previously frequent in HIV-positive patients [31]
propidium iodide (PI), ascertaining that, with their pleiotropic effects, human immunodeficiency virus protease inhibitors (HIV-PI) directly influence pathways involved in tumor cell survival and proliferation, angiogenesis, invasion, and inflammation [5,33]
Summary
FDA-approved human immunodeficiency virus 1 protease inhibitors (HIV-PI) are used in highly active antiretroviral therapy (HAART) that significantly improves the clinical conditions of HIV patients [1,2]. 10 small molecules, i.e., saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir and darunavir, all containing a mimicked peptide bond, have been designed to target the viral protease [3] and they are extensively used in the treatment of AIDS. In addition to the antiviral properties, several preclinical and clinical trials have highlighted pleiotropic effects of these molecules in malignancies not related to HIV, suggesting that they have a pharmacological potential as antitumor agents in both virus- and nonvirus-associated cancers [4,5]. HIV-PIs have been shown to counteract, among others, Kaposi sarcoma [6], multiple myeloma, breast cancer, and ovarian cancer [7,8,9,10,11,12,13,14]
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