Abstract
Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.
Highlights
Despite a large number of molecules approved as anticancer drugs, cancer remains a serious cause of death worldwide [1]
This work aimed to evaluate whether Heme oxygenase-1 (HO-1) inhibitors and σR ligands, as well as a combination of the two, may counteract cancer cell proliferation
We selected DU145 cells as representative for prostate cancer [37], and U87MG as cancer cells of glioblastoma [39], to evaluate whether inhibition of heme oxygenase (HO)-1 and modulation of σRs may be effective for anticancer activity
Summary
Despite a large number of molecules approved as anticancer drugs, cancer remains a serious cause of death worldwide [1]. It is generally accepted that, for anticancer activity, antagonism at σ1R or agonism at σ2R are preferable [34,35] On these premises, this work aimed to evaluate whether HO-1 inhibitors and σR ligands, as well as a combination of the two, may counteract cancer cell proliferation. In our σ1R lead compounds, SI1/13 and RFB/13, the benzyl group linked to piperazine represents HYD2, the N-4 of piperazine is the basic nitrogen, and the other phenyl ring acts as HYD1 These moieties were maintained in our HO-1/σRs hybrids 1–4; while an imidazole linked by an oxybutyl chain was further added with the aim of targeting the HO-1 enzyme. According to Glennon’s pharmacophoric σ1R model [52], HYD1 can tolerate bulky groups; the presence of a flexible 4-(imidazolyl)butoxy group as a substituent might interfere through a steric hindrance in establishing essential hydrophobic interaction between the phenyl ring (located at the HYB1) and key amino acid residues inside the binding pockets
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