Ovarian cancer is the seventh most common cancer type amongst women 1 and the most common histological subtype is high-grade serous cancer (HGSC) 2. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months.

Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in ОіH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Synergy was independent of chloroxineвЂ™s predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths.

Ic 756 pro ii anti-static mod