Abstract
Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.
Highlights
A library of hydrogen sulfide (H2S)-releasing doxorubicin analogues was synthesized to overcome the well-known cardiotoxicity (Sawicki et al, 2021) and the drug resistance (Assaraf et al, 2019) characterizing doxorubicin (Dox) treatment and limiting its use in cancer therapy (Chegaev et al, 2016)
The results obtained for Sdox (Figure 1) were compared to those calculated for Dox to help in assessing the reliability of predictions
Dox, discovered in the late 1960s, still represents the mainstay for the treatment of numerous solid and hematological malignancies, despite its therapeutic value being hampered by cross-resistance towards different anticancer drugs and severe dose-dependent cardiotoxicity
Summary
A library of hydrogen sulfide (H2S)-releasing doxorubicin analogues was synthesized to overcome the well-known cardiotoxicity (Sawicki et al, 2021) and the drug resistance (Assaraf et al, 2019) characterizing doxorubicin (Dox) treatment and limiting its use in cancer therapy (Chegaev et al, 2016). A series of derivatives, devoid of toxicity in H9c2 cardiomyocytes, but still retaining their efficacy in U-2OS osteosarcoma cells, characterized by increasing levels of P-glycoprotein (P-gp) and resistance to Dox, have been synthesized (Chegaev et al, 2016). In U-2OS and Saos-2-chemoresistant osteosarcoma cells, Sdox, unlike Dox, accumulated within the endoplasmic reticulum (ER), where it releases H2S that sulfhydrated nascent proteins, including P-gp, increasing their misfolding and triggering ER-dependent apoptosis (Buondonno et al, 2019). This process enhanced both retention and toxicity of Sdox in resistant cells. To a greater extent, Sdox in a liposomal formulation decorated with hyaluronic acid (HA-Lsdox) reduced the growth of osteosarcoma refractory to both Dox and Caelyx®, the pegylated liposomal Dox, currently used in clinical setting (Gazzano et al, 2019)
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