Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer
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Volume
12
Publisher
Publisher URL
DOI
10.1038/s41419-021-03665-0
Journal
CELL DEATH & DISEASE
Issue
ISSN
2041-4889
Metadata
Show full item recordAbstract
High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to
platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can
circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the
hydroxyquinoline drug, chloroxine. 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.
Synergy was independent of chloroxine’s predicted ionophore activity and did not relate to platinum uptake as
measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides
DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug
alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover,
this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-
mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone
resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and
carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel
results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since
chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.