Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: HUMANGGP:023380 (
carbonic anhydrase XII
)
24
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The role of
carbonic anhydrase XII
(
CAXII
) in the chemoresistance of glioblastoma is unexplored. We found
CAXII
and
P-glycoprotein
(Pgp) coexpressed in neurospheres derived from 3 of 3 patients with different genetic backgrounds and low response to temozolomide (time to recurrence: 6-9 months).
CAXII
was necessary for the Pgp efflux of temozolomide and second-line chemotherapeutic drugs, determining chemoresistance in neurospheres. Psammaplin C, a potent inhibitor of
CAXII
, resensitized primary neurospheres to temozolomide by reducing temozolomide efflux via Pgp. This effect was independent of other known temozolomide resistance factors present in the patients. The overall survival in orthotopic patient-derived xenografts of temozolomide-resistant neurospheres, codosed with Psammaplin C and temozolomide, was significantly increased over temozolomide-treated (
P
< 0.05) and untreated animals (
P
< 0.02), without detectable signs of systemic toxicity. We propose that a
CAXII
inhibitor in combination with temozolomide may provide a new and effective approach to reverse chemoresistance in glioblastoma stem cells. This novel mechanism of action, via the interaction of
CAXII
and Pgp, ultimately blocks the efflux function of Pgp to improve glioblastoma patient outcomes.
...
PMID:Carbonic Anhydrase XII Inhibitors Overcome P-Glycoprotein-Mediated Resistance to Temozolomide in Glioblastoma. 3025 83
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 ( K
i
= 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.
...
PMID:Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma. 3092 64
A new series of
N,N
-bis(alkanol)amine aryl diesters was synthesized and studied as dual
P-glycoprotein
(
P-gp
) and
carbonic anhydrase XII
inhibitors (CA XII). These hybrids should be able to synergistically overcome
P-gp
mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of
P-gp
could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in
P-gp
ATPase activity. The new compounds reported here feature both
P-gp
and CA XII binding moieties. These hybrids contain a
N,N
-bis(alkanol)amine diester scaffold found in
P-glycoprotein
ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against
P-gp
and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both
P-gp
and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds
7
and
8
showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only
P-gp
. They can be considered as valuable candidates for selective
P-gp
/CA XII inhibition in MDR cancer cells.
...
PMID:Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells. 3229 Feb 81
