A triple combination gemcitabine + romidepsin + cisplatin to effectively control triple-negative breast cancer tumor development, recurrence, and metastasis

Abstract

Purpose: Triple-negative breast cancer (TNBC) is an aggressive, lethal, heterogeneous type of breast cancer (BC). TNBC tends to have a lower response rate to chemotherapy and a lower 5-year survival rate than other types of BC due to recurrence and metastasis. Our previous study revealed that a combination of gemcitabine, romidepsin, and cisplatin was efficacious in controlling TNBC tumor development. In this study, we extended our investigation of gemcitabine + romidepsin + cisplatin in controlling TNBC tumor recurrence and metastasis.

Methods: We investigated the ability of gemcitabine + romidepsin + cisplatin to control cell survival and invasiveness using cell viability, soft agar colony formation, and transwell invasion assays. We determined the efficacy of gemcitabine + romidepsin + cisplatin in controlling tumor recurrence and metastasis using cell-derived xenograft animal models. We used immunoblotting to study signaling modulators regulated by gemcitabine + romidepsin + cisplatin in TNBC cells and tumor tissues.

Results: Treatment with gemcitabine + romidepsin + cisplatin reduced the TNBC MDA-MB231 and MDA-MB468 cell survival to ~ 50% and ~ 15%, as well as invasiveness to ~ 31% and ~ 13%, respectively. Gemcitabine + romidepsin + cisplatin suppressed modulators involved in epithelial-mesenchymal transition in an ROS-dependent manner. Controlling tumor recurrence, the Gem plus Rom + Cis regimen (~ 112%) was more efficacious than the Gem plus Cis regimen (~ 21%) in tumor growth inhibition. The Gem plus Rom + Cis regimen efficaciously reduced the development of metastatic nodules to 20% in animals.

Conclusion: The gemcitabine plus romidepsin + cisplatin regimen was highly efficacious in controlling TNBC tumor development, recurrence, and metastasis in animals. The combination regimen should be poised for efficient translation into clinical trials for controlling the recurrence and metastasis, ultimately contributing to reducing mortality and improving TNBC patients' quality of life.

Keywords: Combination regimens; Metastasis; Reactive oxygen species; Recurrence; Triple-negative breast cancer.