Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma

Abstract

Carbonic anhydrase IX (CAIX) is involved in pathological processes including tumorgenicity, metastases and poor survival in solid tumors. Twenty-two neuroblastoma samples of patients who were surgically treated at the University Medical Center Hamburg-Eppendorf were evaluated immunohistochemically for expression of CAIX. Results were correlated with clinical parameters and outcome. Neuroblastoma Kelly and SH-EP-Tet-21/N cells were examined for CAIX expression and inhibited with specific inhibitors, FC5-207A and FC8-325A. 32% of neuroblastoma tumors expressed CAIX. This was significantly associated with poorer survival. Kelly and SH-EP-Tet-21/N cells showed a major increase of CAIX RNA under hypoxic conditions. Proliferation of Kelly cells was significantly decreased by CAIX inhibitors, FC5-207A and FC8-325A, while proliferation of SH-EP-Tet-21/N cells was only significantly affected by FC8-325A. CAIX is a potent biomarker that predicts survival in neuroblastoma patients. CAIX-targeted therapy in neuroblastoma cell lines is highly effective and strengthens the potential of CAIX as a clinical therapeutic target in a selected patient collective.

A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model

“…CAIX is expressed in specific types of tumors as a mediator of the complex response to the low-oxygen environment [ 66 ]. In NB, a correlation between up-regulation of CAIX expression and poor survival, particularly in MYCN -amplified tumors, has been shown [ 89 , 90 ]. Our study revealed that the strong inhibition of angiogenesis by the KD combined with low-dose cyclophosphamide did not stimulate a hypoxic response in NB.…”

The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy

“…Thus, CAIX expression represents a common cancer cell adaptation to changes in tumour microenvironment, such as hypoxia and acidosis, both involved in cancer progression and resistance. CAIX expression in human tumour samples is always associated with tumour progression and poor prognosis 12–16 and its block through chemical inhibitors, either as a single treatment or in combination with radiotherapy, significantly reduces tumour growth in vivo 17 , 18 . Moreover, CAIX targeting by Acetazolamide treatment enhances the anti-angiogenic effect of Bevacizumab 19 .…”

Synthesis of 4,5-disubstituted-2-thioxo-1,2,3,4-tetrahydropyrimidines and investigation of their acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase I/II inhibitory and antioxidant activities

“…These CA families are found in most living organisms. For example a-CAs are found in humans and other mammals and divided into four broad subgroups, which, in turn consist of several isoforms: the cytosolic CAs (CA I, II, III, VII, and XIII), mitochondrial CAs (CA VA and VB), secreted CA (CA VI), as well as membraneassociated CAs (CA IV, IX, XII, XIV and XV) [20][21][22][23][24] . There are three additional, acatalytic CA isoforms (CA VIII, X, and XI) whose functions remain unclear.…”