Abstract
BackgroundPD-0332991, the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, causes cell cycle arrest by inhibiting phosphorylation of retinoblastoma (Rb) protein. The aim of this study was to evaluate the therapeutic potential of PD-0332991 in endometrial cancer.Methods and findingsFour human endometrial cancer cell lines, ECC, HEC1A, HEC108 and TEN, were treated with PD-0332991 and their function was evaluated. In vivo, the therapeutic efficacy was evaluated in a model of subcutaneous endometrial cancer. An immunohistochemical analysis was performed in 337 endometrial cancer specimens. A proliferation assay revealed that 2 of the 4 cell lines that expressed Rb were sensitive to PD-0332991 with an IC50 of 0.65 μM (HEC1A) and 0.58 μM (HEC108), respectively. Both cell lines had G0/G1 cell cycle arrest after treatment with PD-0332991 according to flow cytometry. In vivo, PD-0332991 had antitumoral efficacy with a reduction in the activity of Ki67 and phosphorylation of Rb. Immunohistochemical analyses revealed that the positive rate of Rb was 67.7%, however, there was no significant relationship between the expression levels of Rb and the tumor grade.ConclusionsPD-0332991 had therapeutic potential against endometrial cancer cell lines expressing Rb protein. Our immunohistochemical analysis revealed that approximately 70% of patients with endometrial cancer might have therapeutic indications for PD-0332991. Of note, the tumor grade had no impact on the indications for treatment.
Highlights
Endometrial cancer is the most common gynecologic malignancy in the United States as well as other developed countries [1]
The tumor grade had no impact on the indications for treatment
The compounds cyclin-dependent kinase (CDK) 4/6 and cyclin D1 release transcription factor E2F from Rb, which results in phosphorylation of Rb and subsequent cell proliferation [9, 10]
Summary
Endometrial cancer is the most common gynecologic malignancy in the United States as well as other developed countries [1]. It has been proposed that endometrial carcinomas are pathogenetically divided into type 1 and type II tumors [2]: estrogen-dependent neoplasms called. Palbociclib in endometrial cancer type I account for 80–85% of all cases and estrogen-independent tumors called type II make up the remaining 10–15% of the cases [3, 4]. 16% of women with endometrial cancer, which is only a small proportion, present with advanced disease [5]. For those patients with recurrent or advanced disease, radiotherapy or chemotherapy may be performed, a desirable prognosis has not yet been attained and new breakthrough treatment is expected. The aim of this study was to evaluate the therapeutic potential of PD-0332991 in endometrial cancer
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