Simvastatin is a promising drug candidate for treatment of ovarian clear cell carcinomas

OncotargetFeb 2 2021

Oncotarget recently published "Simvastatin is a potential candidate drug in ovarian clear cell carcinomas" which reported that based on previous studies, the authors assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer cell line, Caov3. The authors used the Rho GTPase interfering drug CID-1067700 as a control.

All OCCC cell lines were more sensitive to single-agent simvastatin than the HGSOC cells, while all cell lines were less sensitive to CID-1067700 than to simvastatin.

Most treatments inhibited migration, while only simvastatin and CID-1067700 also disrupted actin organization in the OCCC cell lines.

Treatments with simvastatin consistently reduced c-Myc protein expression in all OCCC cell lines and displayed evidence of causing both caspase-mediated apoptotic cell death and autophagic response in a cell line dependent manner.

Conclusively, simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.

"Simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC."
Dr. Ingrid Hedenfalk from The Lund University said, "Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) accounting for 5–10% of cases diagnosed in Europe and America, while the incidence in Asia is reported to be higher (10–20%)."

The Oncotarget authors recently reported Rho GTPases and their associated pathways to be differentially expressed between OCCC compared to the other major EOC subtypes.

Rho GTPases have been studied as targets for cancer treatment in various settings due to their role in regulating key cellular functions including the maintenance of cytoskeletal integrity, cell migration and proliferation, but also in metastasis and progressive disease in many cancer types.

However, targeting Rho GTPases directly is challenging due to their high binding affinity for GTP/GDP, and indirect strategies such as targeting the localization of Rho GTPases to the cell membrane are promising alternatives.

CID-1067700 is a pan-GTPase inhibitor that inhibits binding of GTP/GDP and downstream binding of Rho GTPases to their targets and is used as a comparator for Rho GTPase interference as a druggable target in OCCC.

Based on the deregulated expression of both Rho GTPases and cytoskeletal pathways in primary human OCCC tumors in our previous work, they investigated the potential of simvastatin, a lipophilic statin, as a targeted treatment in OCCC cell lines with CID-1067700 as a comparator in the present study.

The Hedenfalk Research Team concluded in their Oncotarget Research Paper that while HGSOC has been studied intensively, OCCC remains a rare subtype with poor prognosis, but this study, although investigative, demonstrates a potential for simvastatin treatment in OCCC.

Simvastatin could act through Rho GTPase interference as simvastatin affects the cytoskeletal integrity of OCCC cells at levels which can be achieved in plasma.

However, the mechanism is different from Rho GTPase inhibition by CID-1067700.

Furthermore, caution should be given, as this data suggest that a combination with standard chemotherapy may elicit an antagonistic response.

Whether this is of clinical relevance for patients receiving statin treatment remains unclear and needs to be investigated further, but simvastatin holds promise as a potential drug candidate in OCCC and warrants further investigation in the clinical setting.