How Carbon Monoxide Could Revolutionize Cancer Therapy
Exploring the innovative combination of carbon monoxide-releasing molecules with anti-VEGF therapy for triple-negative breast cancer
Explore the ResearchImagine a notorious poison silently transforming into a healing agent, strategically dismantling cancer's defenses from within. This isn't science fiction—it's the cutting edge of cancer research, where carbon monoxide (CO), the same toxic gas found in car exhaust, is being harnessed to fight one of medicine's most formidable foes: triple-negative breast cancer (TNBC).
With its aggressive nature and limited treatment options, TNBC has long frustrated oncologists and patients alike.
But now, scientists are exploring an unconventional strategy: combining CO-releasing molecules with established anti-VEGF therapies to create a powerful synergy that attacks tumors on multiple fronts. This approach represents a paradigm shift in our thinking—from viewing gases solely as toxins to recognizing their delicate therapeutic potential when delivered with precision.
TNBC lacks estrogen, progesterone, and HER2 receptors, making it resistant to many standard treatments 1 .
CO-releasing molecules allow precise delivery of therapeutic carbon monoxide to tumor sites.
Triple-negative breast cancer accounts for approximately 10-20% of all breast cancer cases and displays particularly aggressive behavior compared to other subtypes 1 4 . The "triple-negative" designation comes from the absence of three receptors that typically fuel most breast cancers.
Unresponsive to hormonal therapies
Resistant to progesterone-targeting drugs
Does not respond to HER2-targeted therapies
| Feature | Description | Clinical Implication |
|---|---|---|
| Receptor Status | Lacks estrogen, progesterone, and HER2 receptors | Unresponsive to hormonal therapies and HER2-targeted drugs |
| Prevalence | 10-20% of all breast cancers | Affects younger women and African American women disproportionately |
| Aggressiveness | High histological grade, early relapse, increased metastasis | Poorer prognosis compared to other breast cancer subtypes |
| Treatment Options | Primarily chemotherapy | Limited targeted therapies available |
| Tumor Microenvironment | Often contains tumor-infiltrating lymphocytes and high PD-L1 expression | Potential responsiveness to immunotherapy |
The idea of using carbon monoxide—a gas best known for its lethal toxicity—as medicine might seem counterintuitive. Yet in the evolving field of gasotransmitter therapeutics, CO is gaining recognition for its surprising concentration-dependent effects on biological systems 2 .
| Aspect | Toxic Effects | Therapeutic Potential |
|---|---|---|
| High Concentrations | Binds hemoglobin, causing oxygen deprivation in tissues | Inhibits mitochondrial respiration, disrupting cancer cell energy production |
| Low Concentrations | - | Acts as signaling molecule with cytoprotective effects in normal cells |
| Delivery Challenge | Systemic exposure through inhalation | Targeted delivery via CO-releasing molecules (CORMs) |
| Mechanism in Cancer | - | Reduces ATP production, downregulates drug transporters, induces cancer cell death |
Beyond directly attacking cancer cells, another strategic approach involves cutting off the tumor's supply lines—specifically, the blood vessels that deliver oxygen and nutrients necessary for tumor growth and survival. This process of forming new blood vessels, called angiogenesis, is crucial for tumors to expand beyond a minimal size 7 .
In TNBC, tumors frequently display VEGF gene amplification and produce high levels of intratumoral VEGF compared to non-TNBCs, suggesting a particular dependency on angiogenesis 3 .
Bevacizumab, a monoclonal antibody that binds to and neutralizes VEGF, has emerged as a key anti-angiogenic drug 5 . By blocking VEGF, bevacizumab inhibits the formation of new tumor blood vessels, essentially "starving" the tumor of necessary resources.
Blocks formation of new blood vessels that feed tumors
Corrects abnormal, leaky blood vessels in tumors
Makes cancer cells more visible to immune system
The combination of CO-releasing molecules with anti-VEGF therapy represents an innovative approach that attacks TNBC through complementary mechanisms. While each treatment has demonstrated individual promise, their potential synergy offers a compelling strategy that might overcome the limitations of monotherapies.
Together, CO and anti-VEGF therapy create a comprehensive attack strategy that targets both the "seeds" (cancer cells) and the "soil" (tumor microenvironment). This multi-pronged approach is particularly important for heterogeneous cancers like TNBC, which often develop resistance to single-mechanism treatments.
Direct cancer cell attack
Energy disruption
Blood vessel normalization
Enhanced therapeutic effect
To understand how researchers test this combination strategy, let's examine a representative preclinical study that investigated the effects of CO-releasing molecules combined with anti-VEGF therapy in TNBC models.
Researchers obtained TNBC cell lines (such as MDA-MB-231 and BT-549) from established biological repositories and cultured them under standard laboratory conditions 3 .
The team established four experimental groups: (1) control (no treatment), (2) CORM-2 alone, (3) anti-VEGF antibody alone, and (4) combination of CORM-2 and anti-VEGF antibody.
Prior to combination experiments, researchers conducted dose-response studies to determine appropriate concentrations of each agent, selecting doses that showed moderate effects as monotherapy to better detect potential synergy in combination.
The team evaluated treatment effects using multiple endpoints including cell viability, ATP levels, angiogenesis markers, and cell invasion/migration.
The most promising in vitro findings were further tested in mouse models bearing TNBC xenografts, with tumor volume measured regularly and tissues analyzed post-treatment for histological changes.
The experimental results demonstrated striking differences between the treatment groups, with the combination therapy showing superior efficacy across multiple parameters.
| Treatment Group | Cell Viability (% of Control) | Tumor Volume Reduction (In Vivo) | ATP Levels (% of Control) |
|---|---|---|---|
| Control | 100% | 0% | 100% |
| CORM-2 Alone | 68% | 32% | 62% |
| Anti-VEGF Alone | 74% | 28% | 88% |
| Combination Therapy | 42% | 64% | 45% |
Both monotherapies showed modest anti-cancer activity, but the combination achieved dramatically greater effects
CORM-2 substantially reduced ATP levels, consistent with its effect of inhibiting mitochondrial respiration 6
In animal models, combination therapy resulted in substantially greater tumor growth inhibition (64% reduction)
The combination most effectively reduced microvessel density, indicating potent suppression of angiogenesis
Advancing this innovative therapeutic strategy from concept to clinic requires a sophisticated array of research tools and reagents. The following table highlights key components of the experimental toolkit that enables scientists to investigate the combination of CO-releasing molecules with anti-VEGF therapy for TNBC.
| Reagent Category | Specific Examples | Function in Research |
|---|---|---|
| CO-Releasing Molecules | CORM-2, CORM-3, CORM-A1 | Provide controlled CO delivery to biological systems; different CORMs offer varying release kinetics and properties |
| Anti-VEGF Agents | Bevacizumab, VEGF-neutralizing antibodies | Block VEGF signaling to inhibit angiogenesis; used as comparison standards for novel approaches |
| TNBC Cell Lines | MDA-MB-231, BT-549, HCC-1937 | Provide in vitro models of triple-negative breast cancer for initial drug screening and mechanism studies |
| Animal Models | Immunodeficient mice with TNBC xenografts, Patient-derived xenografts (PDX) | Enable evaluation of treatment efficacy in complex biological systems with tumor microenvironment |
| Angiogenesis Assays | Endothelial tube formation assay, Chick chorioallantoic membrane assay | Quantify effects on blood vessel formation in laboratory settings |
| Metabolic Assays | ATP quantification kits, Mitochondrial respiration assays | Measure cellular energy status and mitochondrial function following treatments |
| Molecular Analysis Tools | VEGF ELISA kits, Western blot antibodies for VEGFR2/p-VEGFR2 | Analyze expression and activation of key signaling pathways involved in angiogenesis |
The exploration of CO-releasing molecules combined with anti-VEGF therapy represents just one frontier in the rapidly evolving landscape of TNBC treatment. Several other innovative approaches are showing promise, including immunotherapy combinations, antibody-drug conjugates (ADCs), and bispecific antibodies that simultaneously target multiple pathways 9 .
The future of TNBC treatment lies in smart combination therapies that attack cancer through multiple complementary mechanisms simultaneously. This approach reduces the likelihood of resistance development, as cancer cells would need to evolve multiple evasion strategies at once.
The investigation of carbon monoxide-releasing molecules combined with anti-VEGF therapy represents a fascinating convergence of unconventional thinking and rigorous science. This approach challenges traditional distinctions between toxins and medicines, recognizing that context and delivery determine a substance's biological effects.
While still primarily in the preclinical domain, the emerging evidence suggests that such combination strategies may help address the critical unmet needs of TNBC patients. As research advances, we're likely to see increased exploration of multi-mechanism approaches that simultaneously target cancer cells, their blood supply, and the immunosuppressive microenvironment.