Antitumor synergy between pazopanib and metformin on lung cancer

The findings of this study indicate that the combination of pazopanib and metformin could be a promising therapeutic strategy for lung cancer treatment.

NSCLC is the most common type of lung cancer, and its prognosis is often poor due to drug resistance and limited response to conventional treatments. The study investigates how combining pazopanib, a tyrosine kinase inhibitor (TKI), and metformin, an antidiabetic drug with emerging anticancer properties, enhances antitumor efficacy by targeting several key molecular pathways.

Pazopanib is an angiogenesis inhibitor that blocks vascular endothelial growth factor (VEGF) receptors, reducing tumor blood supply and growth. However, its effectiveness is often limited by drug resistance and significant side effects, such as hypertension and liver toxicity. On the other hand, metformin, widely used in diabetes management, has shown promise in cancer treatment by altering the tumor’s immune microenvironment and affecting pathways critical to cancer cell survival.

Synergistic Effects and Mechanisms

Inhibition of p-Akt/NF-κB/IL-6/STAT3 Pathway: The study demonstrates that the combination of pazopanib and metformin significantly suppresses the p-Akt, NF-κB, IL-6, and STAT3 pathways, which are crucial for cancer cell survival, proliferation, and immune evasion. The inhibition of these pathways leads to reduced tumor growth and enhances the sensitivity of lung cancer cells to the treatment. Specifically, the study found that metformin's ability to modulate these pathways amplifies the effects of pazopanib, resulting in a synergistic impact.

Downregulation of HIF1α/VEGF Pathway: Both pazopanib and metformin target the HIF1α/VEGF signaling axis, which is vital for angiogenesis, the process by which tumors develop new blood vessels to support their growth. By downregulating VEGF expression, the drug combination reduces angiogenesis, limiting the tumor's ability to grow and metastasize. This finding suggests that pazopanib's anti-angiogenic effect is enhanced when combined with metformin, offering a stronger therapeutic approach for inhibiting tumor vascularization.

Suppression of TLR2/TGF-β/PD-L1 Axis: The study highlights the role of the TLR2/TGF-β/PD-L1 axis in promoting immune evasion by cancer cells. PD-L1, in particular, allows tumors to escape immune detection by inhibiting cytotoxic T cells. The combination of pazopanib and metformin significantly suppresses PD-L1 expression, enabling the immune system to more effectively recognize and attack cancer cells. This is particularly important in enhancing the effectiveness of immune-based therapies, which rely on the body's own immune response to eliminate tumors.

Induction of Apoptosis: Apoptosis, or programmed cell death, is a critical mechanism by which cancer therapies kill tumor cells. The study reports that the pazopanib-metformin combination induces higher levels of apoptosis in lung cancer cells by increasing the activity of caspase-3, an enzyme central to the apoptotic process. This finding aligns with the observed reduction in tumor growth and progression in treated cells and animal models.

Enhancement of CD8+ T Cell Infiltration: The study also notes that combination therapy enhances the infiltration of CD8+ cytotoxic T cells into the tumor microenvironment. CD8+ T cells play a key role in targeting and destroying cancer cells. By increasing CD8+ T cell presence, the treatment boosts the immune system’s ability to combat lung cancer.

These findings provide a strong rationale for further clinical investigation of this combination in cancer therapy.

References

Abdallah FM, Ghoneim AI, Abd-Alhaseeb MM, Abdel-Raheem IT, Helmy MW. Unveiling the antitumor synergy between pazopanib and metformin on lung cancer through suppressing p-Akt/ NF-κB/ STAT3/ PD-L1 signal pathway. Biomed Pharmacother. 2024 Sep 26;180:117468. doi: 10.1016/j.biopha.2024.117468. Epub ahead of print. PMID: 39332188.