Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness.

Heejin Lee,Dong-Seok Lee,Sang-Hyun Min,Jun Woo Kim

doi:10.3390/ijms21197379

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/β-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function.

Highlights

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths among women worldwide, and it has the highest mortality rate of all gynecological malignancies [1,2]
The effects of poziotinib and manidipine on ovarian cancer stem cells (CSCs) were tested in A2780-SP cells and SKOV3-SP cells, which were generated from A2780 and SKOV3 cells, respectively, cultured in low-attachment conditions in CSC medium
After calculating the concentrations of poziotinib and calcium channel blockers (CCBs) that caused 50% cell growth inhibition, we selected 10 nM (SKOV3 and SKOV3-SP cells) and 20 nM (A2780 and A2780-SP cells) poziotinib to reduce the viability of ovarian CSCs by 10–20% as a single agent, and a range of CCB concentrations (0–30 μM), for use in further experiments

Summary

Introduction

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths among women worldwide, and it has the highest mortality rate of all gynecological malignancies [1,2]. Ovarian cancer therapy is more effective than therapies for other cancers, and it usually comprises surgery, chemotherapy, and sometimes radiotherapy [3,4]. Chemotherapy for ovarian cancer typically consists of platinum-based and taxane-based drugs [5,6]. PARP inhibitors, such as olaparib and niraparib, are used as targeted therapies [7,8]. Despite these treatment options, 50–70% of patients experience recurrence after treatment [9]. The recurrence may be explained by cancer stem cell (CSC) theory [10]. CSCs possess self-renewal ability and are resistant to chemotherapy and radiotherapy [12,13,14]. The elimination of ovarian CSCs is important for the prevention of ovarian cancer recurrence and prolongation of the survival of patients with ovarian cancer

Methods

Results

Conclusion