Adding acetazolamide to chemotherapy temozolomide for glioblastoma increased sensitivity to treatment and improved survival in animal models.
Acetazolamide (Diamox) is commonly used to treat altitude sickness, but researchers may have found another potential use for the drug in the treatment of aggressive brain tumors, according to a recent study.
Researchers have found that acetazolamide may provide clinical benefit to patients with glioblastoma by increasing sensitivity to treatment and enhancing survival. The drug, which is a carbonic anhydrase inhibitor, can restore the ability of chemotherapy temozolomide (TMZ) to kill tumor cells.
The study, published in Science Translational Medicine, found that adding acetazolamide to TMZ treatment enabled mice with gliomas to survive longer.
Although TMZ is frequently used to treat patients with this disease, the drug is not effective in all patients. Its impact is limited by the ability of some tumor cells to block or repair DNA damage caused by the treatment to kill tumor cells, the researchers noted. According to the study, most patients with high levels of a protein called B cell CLL/lymphoma 3 (BCL-3) are unresponsive to the effects of TMZ.
The researchers tested the combination of TMZ and acetazolamide in several animal models.
Overall, the researchers found that the combination treatment cured some of the animals, while others had a 30% to 40% increase in survival time. In previous human studies, patients with lower levels of BCL-3 who were treated with TMZ survived longer than patients who had higher levels, indicating that this marker can be used to determine which patients may benefit the most from this treatment. In mice injected with high BCL-3 expressing human gliomas, acetazolamide increased sensitivity to TMZ and survival in the mouse model.
“An important feature of predictors like BCL-3 is that they are informative,” the researchers wrote. “They can identify pathways to improve treatment response.”
Although the results are promising, the researchers noted that a prospective randomized clinical trial is needed to validate the use of BCL-3 to predict which patients will benefit from treatment with TMZ.
“Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas,” the researchers concluded.
Wu L, Bernal GM, Cahill KE, et al. BCL3 expression promotes resistance to alkylating chemotherapy in gliomas. Science Translational Medicine. 2018. Doi: 10.1126/scitranslmed.aar2238