Abstract
Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB-231, FaDu, HT29 –CAIX high and HT29 –CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 µM, p = 0.0003). Similar results were observed for HT29—CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 µM, p<0.0001) and in the HT29 –CAIX low cells (IC50 is 0.09 µM, p<0.0001). In vivo doxorubicin treatment was only effective in the MDA-MB-231 xenografts, but the efficacy of doxorubicin was decreased when combined with S4. In conclusion, the efficacy of doxorubicin treatment can be increased when combined with the selective sulfamate CAIX inhibitor S4 in vitro in certain cell lines. Nevertheless, in xenografts S4 did not enhance doxorubicin efficacy in the FaDu and HT29 tumor models and decreased doxorubicin efficacy in the MDA-MB-231 tumor model. These results stress the importance of better understanding the role of CAIX inhibitors in intratumoral pH regulation before combining them with standard treatment modalities, such as doxorubicin.
Highlights
The immature and inadequate vasculature of solid tumors prevents oxygen and nutrients supply to certain areas in those tumors
While S4 did not increase the sensitivity of MDA-MB-231 cells during normoxia, IC50 reduced to 0.14 μM during hypoxia (p = 0.0003), suggesting that S4 mediated carbonic anhydrase IX (CAIX) inhibition increases doxorubicin efficacy during hypoxia exposure in MDA-MB-231 cells
Similar results were obtained for protein expression of CAIX which was decreased by doxycycline exposure of HT29 cells both in normoxia and hypoxia (Fig 2B and 2C)
Summary
The immature and inadequate vasculature of solid tumors prevents oxygen and nutrients supply to certain areas in those tumors. This hypoxic microenvironment selects for a more aggressive tumor phenotype and promotes invasion, migration, and thereby metastases formation [1, 2]. The important role that CAIX plays in maintaining the cellular pH balance combined with its predominant expression on hypoxic tumor cells make it an attractive target for treatment [2, 4, 5, 10]. Several CAIX inhibitors have been shown to be effective in reducing primary tumor growth in vivo, either as a single treatment or in combination with radiotherapy [15,16,17]
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