Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity
Giuseppe Romeo1, Valeria Ciaffaglione1, Emanuele Amata1
1Department of Drug and Health Sciences, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
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.
Insights
Targeting heme oxygenase-1 (HO-1) and sigma receptors (σRs) simultaneously with novel hybrid compounds shows increased anticancer activity against prostate and glioblastoma cells. This dual targeting strategy offers a promising new approach for cancer treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are overexpressed in various human cancers, promoting tumor progression.
- Targeting these pathways individually has shown potential in cancer therapy.
Purpose of the Study:
- To investigate the antiproliferative effects of HO-1 inhibitors and σR ligands, individually and in combination, on cancer cells.
- To synthesize and evaluate novel hybrid compounds targeting both HO-1 and σRs.
Main Methods:
- DU145 (prostate) and U87MG (glioblastoma) cancer cell lines were treated with HO-1 inhibitors, σR ligands, and novel hybrid compounds (1-4).
- Cell proliferation was assessed to determine antiproliferative activity.
- Hybrid compounds were synthesized and characterized.
Main Results:
- Simultaneous targeting of HO-1 and σRs demonstrated enhanced antiproliferative activity against DU145 and U87MG cells compared to single-target agents.
- Novel hybrid compounds (1-4) were successfully synthesized and exhibited dual inhibitory potential.
- The combination therapy proved more effective than individual treatments.
Conclusions:
- Simultaneous inhibition of HO-1 and σRs is a viable strategy for developing novel anticancer agents.
- The synthesized HO-1/σR hybrid compounds represent a promising starting point for further optimization.
- This dual-targeting approach offers a potential new avenue for treating prostate and glioblastoma cancers.
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