Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment.
Dotan MoskovichYael FinkelshteinAdi AlfandariAmit RosemarinTzuri LifschytzAvivit WeiszSantanu MondalHarinarayana UngatiAviva KatzavDebora KidronGovindasamy MugeshMartin EllisBernard LererOsnat Ashur-FabianPublished in: Oncogene (2021)
The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (OVCAR3 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and OVCAR3 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian cancer and potentially other DIO3-dependent malignancies.
Keyphrases
- high grade
- cell proliferation
- cell cycle arrest
- signaling pathway
- induced apoptosis
- squamous cell carcinoma
- stem cells
- poor prognosis
- end stage renal disease
- newly diagnosed
- lymph node
- prognostic factors
- high throughput
- single cell
- bone marrow
- pi k akt
- smoking cessation
- low grade
- cancer therapy
- high density
- patient reported
- protein kinase