Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness

Abstract

Carbonic anhydrase IX (CA-IX) plays a pivotal role in regulation of pH in tumor milieu catalyzing carbonic acid formation by hydrating CO2. An acidification of tumor microenvironment contributes to tumor progression via multiple processes, including reduced cell-cell adhesion, increased migration and matrix invasion. We aimed to assess whether the pharmacological inhibition of CA-IX could impair tumor cell proliferation and invasion. Tumor epithelial cells from breast (MDA-MB-231) and lung (A549) cancer were used to evaluate the cytotoxic effect of sulfonamide CA-IX inhibitors. Two CA-IX enzyme blockers were tested, SLC-0111 (at present in phase Ib clinical trial) and AA-06-05. In these cells, the drugs inhibited cell proliferation, migration and invasion through shifting of the mesenchymal phenotype toward an epithelial one and by impairing matrix metalloprotease-2 (MMP-2) activity. The antitumor activity was elicited via apoptosis pathway activation. An upregulation of p53 was observed, which in turn regulated the activation of caspase-3. Inhibition of proteolytic activity was accompanied by upregulation of the endogenous tissue inhibitor TIMP-2. Collectively, these data confirm the potential use of CA-IX inhibitors, and in particular SLC-0111 and AA-06-05, as agents to be further developed, alone or in combination with other conventional anticancer drugs.

A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity

“…Furthermore, RC44 caused a strong inhibition of cell migration and invasiveness, reducing the metastatic potential of TNBC. These results are in agreement with those recently reported by Ciccone et al that show how the pharmacological inhibition of CA IX induces tumor cell death by activating the apoptotic pathway involving p53 and caspase-3, and reduces cell invasion, inducing the switch from the mesenchymal phenotype toward an epithelial one [38]. Recently, Guerrini et al reported the involvement of CA XII in TNBC progression through its crosstalk with hedgehog pathway [39]; therefore, given that RC44 is able to inhibit also this isoform, we believe that this molecule may be more helpful in the treatment of this aggressive carcinoma.…”

Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells

“…CAIX inhibition has been validated recently as a new approach for targeting hypoxic tumours, with at least one compound in Phase Ib/II clinical trials [ 18 , 20 , 21 , 22 , 23 ]. Understanding the role of CAIX at various stages of cancer development (e.g., metabolic transformation, growth, invasion, and metastasis) and investigating functional and biomolecular changes associated with CAIX inhibition are critical for drug development [ 24 , 25 ]. As mentioned above, hypoxia-induced CAIX plays a role in intracellular and extracellular pH regulation [ 26 ], whereas CAIX is ectopically expressed by most hypoxic tumour types in advanced stages of the disease [ 7 ].…”

Tissue Expression of Carbonic Anhydrase IX Correlates to More Aggressive Phenotype of Basal Cell Carcinoma

“…Among the molecules most expressed in hypoxic condition, the carbonic anhydrase IX (CAIX) is considered a marker of hypoxia in vivo (17), whose overexpression has been correlated with increased tumor aggression in different types of cancer (18)(19)(20)(21)(22). To date, a series of CAIX inhibitors have been synthesized, both in the form of small inhibitory molecules and as monoclonal antibodies, used as antitumor agents in different models of neoplasms (23)(24)(25)(26)(27)(28)(29)(30)(31). In a previous work we tested the expression of CAIX in several human solid tumors, extending the CAIX expression information to the expression of the stem cells markers CD44 and nestin in solid cancers, to explore their relationship with the biological behavior of tumors.…”