Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer

Small cell lung cancer (SCLC) has an extremely poor prognosis and methods of improving chemotherapeutic intervention are much sought after. A promising approach lies in inhibiting the tumour-associated enzyme, carbonic anhydrase IX (CA IX), which supports tumour cell survival. The aim of this study was to assess the potential of CA IX inhibition using 4-(3-(3,5-dimethylphenyl)ureido)phenyl sulfamate (S4), for the treatment of human SCLC alone and in combination with cisplatin chemotherapy. Treating SCLC cell lines (DMS 79 and COR-L24) with 100 mu M S4 reduced viability in vitro and enhanced cell death when combined with 7 mu M cisplatin, most prominently under hypoxic conditions (0.1% O-2). When either cell line was grown as a xenograft tumour in nude mice, intraperitoneal injection of 50 mg/kg S4 alone and in combination with 3 mg/kg cisplatin led to significantly reduced tumour growth. Combination therapy was superior to single agents and response was greatly accentuated when administering repeated doses of cisplatin in DMS 79 tumours. The mechanism of therapeutic response was investigated in vitro, where S4 treatment increased apoptosis under hypoxic conditions in both DMS 79 and COR-L24 cells. DMS 79 tumours receiving S4 in vivo also displayed increased apoptosis and necrosis. Combining S4 with cisplatin reduced both the area of hypoxia and CA IX-positive cells within tumours and increased necrosis, suggesting hypoxia-specific targeting. This study presents a novel, targeted approach to improving current SCLC therapy via inhibition of CA IX, which enhances apoptosis and significantly inhibits xenograft tumour growth when administered alone and in combination with cisplatin chemotherapy.What's new? Small-cell lung cancer (SCLC) treatment has not significantly progressed over the past 30 years, but targeted therapy now has the potential to improve patient outcomes. In this study, the authors found that response to cisplatin was markedly enhanced both in vitro and in vivo through combination treatment with a novel small-molecule inhibitor of carbonic anhydrase IX (CA IX). This response was associated with increased apoptosis and necrosis, possibly via hypoxia-specific targeting. These results suggest that inhibiting CA IX may offer a new therapeutic strategy in SCLC patients receiving chemotherapy.