Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

Abstract

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.

Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation

“…Some of these drugs have been reported to have anti-cancer effects. For example, harmaline can suppress the growth of liver cancer cells by inducing the p53/p21 and Fas/FasL signaling pathways [ 25 ], and may have therapeutic potential for controlling breast cancer invasiveness [ 26 ], and chloroxine can facilitate platinum-induced DNA damage to induce cancer cell death in high-grade serous cancer [ 27 ]. Therefore, the prediction of DERIGs-related drugs as a good reference advances our future scientific research.…”

Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

“…To screen HGSC cell lines for existing drugs that synergise with dl 922-947, we used a 96-well cell viability assay based on our previous work 61 , 62 . Our library includes 1177 small molecules (Selleck Chemicals), in which 90% are marketed drugs, and the remaining 10% are bioactive alkaloids.…”

“…After 24 h, cells were treated with either dl 922-947 (MOI (multiplicity of infection) of ten plaque-forming units (pfu) per cell) or vehicle control. Then at 48 h and again at 120 h, cells were treated with the library (10 μM based on our previous work 61 , 62 ) or dimethyl sulphoxide (DMSO) vehicle control. Each drug in the compound library was therefore tested alone and in combination with dl 922-947 in all three cell lines, in one well of the 96-well plate per experimental condition.…”

“…< −2 following library + dl 922-947 together with s.f. > −2 for library compound alone 62 . Using these criteria, six compounds were identified as potential hit drugs in both Ov4Cis and Ov4Carbo cells (Supplementary Data 3 ).…”