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Structural Modifications on CORM-3 Lead to Enhanced Anti-angiogenic Properties Against Triple-negative Breast Cancer
Malamati Kourti1, Jun Cai1, Wen Jiang1
1Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom.
Purpose:
Carbon monoxide-releasing molecules (CORMs) are a special class of organometallic complexes that have been reported to offer beneficial effects against different conditions including several subtypes of cancer. Especially for the aggressive and poorly treated triplenegative breast cancer (TNBC), early CORMs have been shown to diminish malignant angiogenesis and may be considered as an alternative approach. So, this study aimed at testing novel CORM molecules against angiogenesis in TNBC seeking potent drug candidates for new therapies.
Methods:
Based on previous studies, CORM-3 was chosen as the lead compound and a group of 15 new ruthenium-based CORMs was synthesized and subsequently evaluated in vitro for potential anti-angiogenic properties.
Results:
A similar anti-angiogenic behaviour to the lead complex was observed and a new CORM, complex 4, emerged as a promising agent from this study. Specifically, this complex offered better inhibition of the activation of VEGFR2 and other downstream proteins of vascular endothelial cells. Complex 4 also retained the ability of the parent molecule to reduce the upregulated VEGF expression from TNBC cells and inhibit endothelial cell migration and new vessel formation. The lack of significant cytotoxicity and the downregulating activity over the cytoprotective enzyme haem oxygenase-1 (HO-1) in cancer cells may also favour CORMs against this poorly treated subtype of breast cancer.
Conclusion:
Since the anti-angiogenic approach is one of the few available targeted strategies against TNBC, both CORM-3 and the new complex 4 should be considered for further research as combination agents with existing anti-angiogenic drugs for more effective treatment of malignant angiogenesis in TNBC.
Insights
Novel carbon monoxide-releasing molecules (CORMs) show promise in combating triple-negative breast cancer (TNBC) by inhibiting angiogenesis. Complex 4 demonstrated potent anti-angiogenic effects, offering a potential new therapeutic strategy for TNBC.
Area of Science:
- Organometallic chemistry
- Cancer biology
- Molecular pharmacology
Background:
- Carbon monoxide-releasing molecules (CORMs) exhibit therapeutic potential in various conditions, including cancer.
- Triple-negative breast cancer (TNBC) is aggressive and poorly treated, with limited therapeutic options.
- CORMs have shown promise in diminishing malignant angiogenesis, a key process in TNBC progression.
Purpose of the Study:
- To synthesize and evaluate novel ruthenium-based CORM molecules for anti-angiogenic properties.
- To identify potent drug candidates for new TNBC therapies targeting angiogenesis.
- To investigate the efficacy of new CORMs against angiogenesis in TNBC models.
Main Methods:
- Synthesis of 15 novel ruthenium-based CORMs, with CORM-3 as the lead compound.
- In vitro evaluation of synthesized CORMs for anti-angiogenic potential.
- Assessment of effects on VEGFR2 activation, VEGF expression, and endothelial cell migration.
Main Results:
- A new CORM, complex 4, exhibited significant anti-angiogenic activity, comparable to CORM-3.
- Complex 4 effectively inhibited VEGFR2 activation and downstream signaling in vascular endothelial cells.
- Complex 4 reduced VEGF expression in TNBC cells and inhibited endothelial cell migration and new vessel formation without significant cytotoxicity.
Conclusions:
- The novel CORM, complex 4, demonstrates potent anti-angiogenic properties and is a promising candidate for TNBC therapy.
- CORMs, including complex 4, warrant further investigation as potential combination agents with existing anti-angiogenic drugs.
- Targeting malignant angiogenesis with CORMs offers a viable strategy for treating TNBC.
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