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.
Highlights
Development of many solid tumors implies the activation of aberrant growth and survival signals that drastically reprogram cancer cell energy metabolism [1]
We examined the basal expression of CA-I, CA-II and Carbonic anhydrase IX (CA-IX) in a panel of cell lines from different cancer tissues: MDA-MB-231, metastatic breast cancer cells, and A549, non-small cell lung cancer cells
As CA-IX is ectopically expressed in tumors, but it is one of the most upregulated gene in a hypoxia inducible factor-1α (HIF-1α) dependent manner [13,20], we assessed the regulation of CA-IX expression in hypoxic condition
Summary
Development of many solid tumors implies the activation of aberrant growth and survival signals that drastically reprogram cancer cell energy metabolism [1]. Deregulated energy metabolism and inadequate perfusion cause the remodeling of tumor microenvironment, including hypoxia, pH balance, changing in glucose and lactate secretion and recruitment of immune and stromal cells [2]. To maintain an intracellular pH (pHi) compatible with cell survival and proliferation, a large family of transporters extrudes the excess of lactate and protons in the extracellular milieu. The pHi is increased compared to normal cells, while the extracellular pH (pHe) is decreased. This “reversed pH gradient” in cancer cells is considered an emerging hallmark of cancer [3], promoting tumor growth and metastasis via various mechanisms. An acidification of pHe can influence the invasive and metastatic potential of tumors by epithelial-mesenchymal transition (EMT) induction [6,7]
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