Given the impelling need for innovative cancer treatment approaches to overcome novel mutations and chemotherapy resistance, a more rapid and not very expensive way seems to be the repositioning of already approved drugs as anticancer agents [Subeha MR et al. (2020) Cancers 12, 3427]. There are several pre-clinical and clinical evidences suggesting that HIV-1 protease inhibitors (HIV-PIs), in addition to the antiretroviral properties, possess pleiotropic pharmacological actions, including anticancer effects [Maksimovic-Ivanic D et al. (2016) Int J Cancer 140, 1713–1726]. Possible use of some derivatives of hydroxyethy lamine, the central nucleus of the HIV-1 protease inhibitor Daru navir, as molecules with pro-apoptotic activity on tumor cells, has been demonstrated [Facchinetti V et al. (2015) Med Chem Res 24, 533–542], and two new analogous molecules, indicated as RDD -19 and RDD-142, have been synthesized. The two mole cules showed a greater and dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-patho logical hepatic cell line IHH, also higher than that shown by treating the cells with Darunavir. Therefore, several assays were performed in order to clarify the molecular mechanisms of their cytotoxic effect. Both molecules caused two types of cell death, a caspase-dependent apoptosis, ascertained by a series of biochemi cal and morphological assays, and a caspase-independent death that was characterized by induction of endoplasmic reticulum stress and autophagy. The strong increase of ubiquitinated pro teins inside the cell suggested that the target of these molecules was the proteasome and in silico molecular docking experiments make this hypothesis plausible. Finally, treating the cells with the two analogs lowered p-AKT levels, interfering with cell survival and proliferation. These findings demonstrate that RDD-19 and RDD-142, two novel Darunavir analogues, are potent anticancer agents with pleiotropic effects
RDD-19 and RDD-142, two novel darunavir analogues, induce apoptosis, ER stress and autophagy in hepatic cancer cells
D'Orsi R.;
2021-01-01
Abstract
Given the impelling need for innovative cancer treatment approaches to overcome novel mutations and chemotherapy resistance, a more rapid and not very expensive way seems to be the repositioning of already approved drugs as anticancer agents [Subeha MR et al. (2020) Cancers 12, 3427]. There are several pre-clinical and clinical evidences suggesting that HIV-1 protease inhibitors (HIV-PIs), in addition to the antiretroviral properties, possess pleiotropic pharmacological actions, including anticancer effects [Maksimovic-Ivanic D et al. (2016) Int J Cancer 140, 1713–1726]. Possible use of some derivatives of hydroxyethy lamine, the central nucleus of the HIV-1 protease inhibitor Daru navir, as molecules with pro-apoptotic activity on tumor cells, has been demonstrated [Facchinetti V et al. (2015) Med Chem Res 24, 533–542], and two new analogous molecules, indicated as RDD -19 and RDD-142, have been synthesized. The two mole cules showed a greater and dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-patho logical hepatic cell line IHH, also higher than that shown by treating the cells with Darunavir. Therefore, several assays were performed in order to clarify the molecular mechanisms of their cytotoxic effect. Both molecules caused two types of cell death, a caspase-dependent apoptosis, ascertained by a series of biochemi cal and morphological assays, and a caspase-independent death that was characterized by induction of endoplasmic reticulum stress and autophagy. The strong increase of ubiquitinated pro teins inside the cell suggested that the target of these molecules was the proteasome and in silico molecular docking experiments make this hypothesis plausible. Finally, treating the cells with the two analogs lowered p-AKT levels, interfering with cell survival and proliferation. These findings demonstrate that RDD-19 and RDD-142, two novel Darunavir analogues, are potent anticancer agents with pleiotropic effectsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
