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Acetazolamide is a synthetic small‐molecule drug primarily known as a carbonic anhydrase inhibitor. Although it is used mainly in treating glaucoma, altitude sickness, and certain neurological conditions, several studies have explored its potential in cancer treatment—mostly by targeting the tumor microenvironment.
Acetazolamide might impact cancer biology:
Carbonic Anhydrase Inhibition
• Acetazolamide inhibits several isoforms of carbonic anhydrase (especially CA IX and CA XII), enzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and protons.
• In many cancers, CA IX is overexpressed in response to hypoxia (mediated by HIF‐1α) and helps maintain an acidic extracellular environment while keeping the intracellular pH relatively neutral. This pH regulation supports cancer cell survival and invasion.
Tumor pH Regulation
• By inhibiting carbonic anhydrases, acetazolamide can disrupt the acid–base balance in the tumor microenvironment.
• An altered pH gradient can impair cancer cell proliferation, migration, invasion, and can influence drug resistance. This disruption may also sensitize tumors to other therapeutic modalities.
Hypoxia and HIF-1 Signaling
• Inhibiting CA IX may indirectly affect downstream targets of the HIF-1 pathway, potentially interfering with processes such as angiogenesis and metabolic adaptation.
Impact on Tumor Metabolism
• The inhibition of carbonic anhydrases may affect the metabolic reprogramming seen in cancer cells.
• Alterations in bicarbonate and proton handling can influence metabolic pathways like glycolysis and oxidative phosphorylation, which are often altered in tumor cells.
Potential Effects on Immune Response
• An acidic tumor microenvironment can contribute to immunosuppression.
• By modifying the pH environment through the inhibition of carbonic anhydrase, acetazolamide might help improve immune cell infiltration and function, although this area is still under investigation.
In summary, while acetazolamide is a synthetic drug and not a natural product, its ability to alter key aspects of tumor biology—such as pH regulation, hypoxia response, and metabolic reprogramming—makes it an interesting candidate for adjuvant cancer therapies. However, its application in oncology remains investigational and would require further clinical validation.