Abstract
Although endometrial carcinoma is one of the most common gynecological malignancies worldwide, its precise etiology remains unknown. Moreover, no novel adjuvant and/or targeted therapies are currently being developed to achieve greater efficacy for endometrial cancer patients who develop chemotherapeutic drug resistance. In this study, we used three human endometrial cancer cell lines, RL95-2, HEC-1-A, and KLE, to investigate the responsiveness of cisplatin alone and in combination with potential repurposed drugs. We first found that RL95-2 cells were more sensitive to cisplatin than HEC-1-A or KLE cells. The cytotoxicity of cisplatin in RL95-2 cells may reflect its ability to perturb the cell cycle, reactive oxygen species production and autophagy as well as to induce senescence and DNA damage. Similar effects, although not DNA damage, were also observed in HEC-1-A and KLE cells. In addition, downregulation of p53 and/or cyclin D1 may also impact the responsiveness of HEC-1-A and KLE cells to cisplatin. We also observed that resveratrol, trichostatin A (TSA), caffeine, or digoxin increased the apoptotic process of cisplatin toward RL95-2 cells, while amiodarone or TSA increased its apoptotic process toward HEC-1-A cells. The combination index supported the assertion that the combination of cisplatin with caffeine, amiodarone, resveratrol, metformin, digoxin, or TSA increases the cytotoxicity of cisplatin in HEC-1-A cells. These findings suggest potential strategies for enhancing the efficacy of cisplatin to overcome drug resistance in endometrial carcinoma patients.
Highlights
Endometrial cancer is the most common of the gynecologic malignancies, with a worldwide prevalence rate estimated to be 10–20% [1]
Cell Lines To better understand the differential responsiveness of endometrial cancer to cisplatin and the potential combination therapy, we assessed its effects on three commercial enTo better understand the differential responsiveness of endometrial cancer to cisplatin and the potential combination therapy,(type we assessed its effects onII), three dometrial cancer cell lines, RL95-2
We found that RL95-2 cells are more sensitive to cisplatin than HEC-1-A
Summary
Endometrial cancer is the most common of the gynecologic malignancies, with a worldwide prevalence rate estimated to be 10–20% [1]. The lesions are usually confined to the uterus, and standard treatment consists of primary hysterectomy and bilateral salpingooophorectomy, as well as adjuvant radiotherapy and chemotherapy in patients with risk factors [2]. The 5-year overall survival rate ranges from 74% to 91% [3]. The overall survival rate is relatively good for patients diagnosed early, the recurrence rate is reportedly 7.7% to 63.3%, and is associated with surgical-pathological risk factors [4]. No novel adjuvant and/or targeted therapies have been developed to achieve greater treatment specificity for these patients or to overcome chemotherapeutic drug resistance
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