Tumor development is a complex, multifactorial process intricately linked to oncogene activation, tumor suppressor gene inactivation, aberrant apoptosis, and dysfunctional DNA damage repair mechanisms. Recently, increasing evidence has highlighted the crucial role of mitochondria in tumorigenesis. As the metabolic hub of the cell, mitochondria are central to the unique metabolic characteristics of cancer cells, which has led to a new focus in anti-cancer research: the development of compounds targeting mitochondrial function.
Among these potential compounds, Nebivolol, a β1-adrenergic receptor antagonist, has emerged as a promising agent due to its ability to inhibit energy metabolism in tumor cells and suppress tumor angiogenesis. Nebivolol has demonstrated substantial potential in oncology as a mitochondrial-targeting anti-cancer agent. Its ability to disrupt energy metabolism and inhibit angiogenesis provides a compelling basis for its application in cancer therapy. As research progresses, Nebivolol could emerge as a key player in the development of novel, metabolism-targeted anti-cancer strategies.
Nebivolol: Mechanisms of Action
Nebivolol is a third-generation β1-adrenergic receptor blocker that has been primarily used in the treatment of mild to moderate hypertension, angina pectoris, and congestive heart failure. However, recent studies have demonstrated its potential anti-tumor activity through dual mechanisms: inhibition of mitochondrial energy metabolism and suppression of angiogenesis.
Fig.1 Nebivolol inhibits mitochondrial metabolism and suppresses tumor growth[1].
Inhibition of Mitochondrial Energy Metabolism
Mitochondria are vital for cellular energy production through oxidative phosphorylation (OXPHOS). In cancer cells, mitochondrial metabolism is often altered to support rapid proliferation and survival under stressful conditions. Nebivolol exerts its anti-tumor effect by targeting this altered mitochondrial metabolism. Specifically, it inhibits the activity of Complex I of the mitochondrial respiratory chain by suppressing the phosphorylation of NDUFS7, a key subunit of Complex I. This inhibition disrupts the electron transport chain (ETC), reducing ATP production and leading to an energy deficit in tumor cells.
Additionally, Nebivolol upregulates the expression of ATPase inhibitory factor 1 (IF1), which inhibits mitochondrial ATP synthase activity. ATP synthase is responsible for the final step of ATP production in mitochondria. By inhibiting ATP synthase, Nebivolol further depletes ATP levels, impairing the energy supply necessary for cancer cell survival and proliferation. This dual inhibition strategy places cancer cells under metabolic stress, ultimately triggering oxidative stress and apoptosis.
Suppression of Tumor Angiogenesis
Angiogenesis, the process of new blood vessel formation, is critical for tumor growth and metastasis as it provides essential nutrients and oxygen to rapidly dividing cancer cells. Nebivolol has been shown to inhibit angiogenesis by suppressing the proliferation of endothelial cells, which form the lining of new blood vessels. This anti-angiogenic effect further starves tumor cells of the resources required for their growth, enhancing the anti-tumor potential of Nebivolol.
Implications for Cancer Therapy
The dual mechanisms by which Nebivolol exerts its anti-tumor effects-targeting both mitochondrial metabolism and angiogenesis—represent a novel and promising approach in cancer therapy. The ability of Nebivolol to induce a metabolic and oxidative stress crisis in tumor cells without significantly affecting normal cells positions it as an attractive candidate for combination therapy. This is particularly relevant in the context of tumors that exhibit high metabolic flexibility and resistance to conventional therapies.
Given the increasing recognition of mitochondrial dysfunction and metabolic reprogramming as hallmarks of cancer, drugs like Nebivolol that target these processes are of significant interest. Future research should focus on elucidating the precise molecular pathways involved in Nebivolol's action, optimizing its dosing and delivery, and evaluating its efficacy across different cancer types.
Reference
- Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth. Nature Communications (2020).
