Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma

The natural product primary sulfonamide,
psammaplin C (1), when used in combination with clinically
used chemotherapeutic
drugs, including temozolomide, reverses multidrug resistance and increases
survival in glioblastoma, a highly aggressive primary brain tumor.
We showed previously that the mechanism of action of 1 is novel, acting to indirectly interfere with P-glycoprotein drug
efflux activity as a consequence of carbonic anhydrase XII (CA XII)
inhibition. To build structure–activity relationships, 45 derivatives
of 1 were designed, synthesized, and evaluated against
a panel of CA isoforms. Compound 55 was identified as
a potent inhibitor of CA XII (Ki = 0.56
nM) and was investigated in vitro and in vivo using samples from glioblastoma
patients. The results strengthen the possibility that co-therapy of
temozolomide with a CA XII inhibitor may more effectively treat glioblastoma
by suppressing an important temozolomide resistance mechanism.