Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Abstract

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (Rs) 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 R 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/Rs) 14 containing the chemical features needed for HO-1 inhibition and R modulation. Herein, we report for the first time that targeting simultaneously HO-1 and R 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/Rs hybrids to develop novel potential anticancer agents.

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

“…Extending this effort, we recently identified SI 1/13, a selective benzylpiperazine-based S1R antagonist with a S2R/S1R selectivity ratio of 886 that demonstrated efficacy against chronic constrictive nerve injury (CCI)-induced neuropathic pain and formalin-induced inflammatory pain without impairing locomotor activity [ 22 ]. In addition, SI 1/13 demonstrated significant cytotoxic effects towards DU145 and U87MG cancer cells, further corroborating its function profile as a S1R antagonist [ 23 , 24 ].…”

D2 dopamine receptor‐mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine

“…Afterwards, the preparations were fixed in a humid incubator at 37°C after being placed in caps filled with vaseline. Then, the preparations were treated with ACSF (control) or apomorphine (10 μM, Himeno et al, 2011), metoclopramide (10 μM, Wolfes et al, 2021), haloperidol (10 μM, Romeo et al, 2021) and ondansetron (10 μM, Hur et al, 2014) or their combinations, respectively; 250 μL of incubation medium was collected for each treatment at 10 min intervals and was mixed with 20 μL of aprotinin to prevent the degradation of CGRP. The aliquots were stored at −20°C until CGRP measurement.…”

Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer

“…In a study conducted by Romeo et al, it was observed that sigma receptors, non-G protein-coupled receptor (GPCR) transmembrane proteins, are expressed in various cancer cell lines. Their two subtypes, σ-1R and σ-2R, are, respectively, antagonized and agonized to promote cancer inhibitory effects [80]. When exposing DU145 cells to sigma receptor ligands, it was found that cell proliferation was noticeably reduced by approximately 50%.…”

“…When exposing DU145 cells to sigma receptor ligands, it was found that cell proliferation was noticeably reduced by approximately 50%. When used in combination with HO-1 receptors, it was found that exposure to 10 µM of both the ligand and inhibitor greatly reduced proliferation by 75% [80]. This response suggests that while targeting the use of either an inhibitor or sigma receptor is effective in the reduction in cell viability, the greatest effect comes from multi-targeted combination therapy.…”

“…Romeo et al have shown that targeting both HO-1 pathways may serve as a novel therapeutic strategy in PCa therapy [80]. The simultaneous targeting of HO-1 and sigma receptor proteins reduces DU145 cell proliferation.…”