Abstract
BackgroundEndometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE.MethodsThe effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509.ResultsBoth AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p = 0.034).ConclusionsOur findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-752) contains supplementary material, which is available to authorized users.
Highlights
Endometrial cancer is the most common gynecologic malignancy
HCI2509 impairs viability, proliferation, and transformation in Type II endometrial cancer cell lines We first validated previous data suggesting that Type II endometrial carcinoma cells were sensitive to Lysine-specific demethylase 1 (LSD1) inhibition with HCI2509 [35]
Both AN3CA and KLE cell lines exhibited a dose-dependent decrease in cell viability after 96 hours of treatment with HCI2509 (Figure 1A, B) with Effective concentration at 50% (EC50) values determined at 499 nM and 435 nM, respectively (Figure 1A, B)
Summary
Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Endometrial carcinoma (EC) arises from the lining of the uterus and is the most commonly diagnosed invasive gynecologic malignancy, exceeding the incidence of cervical, ovarian, vaginal, and vulvar cancers combined [1,2]. With 50,230 new cases and 8,590 deaths estimated in the U.S for 2014 it is the fourth most prevalent cancers present and are diagnosed in earlier stages and are typically more differentiated, responsive to progesterone treatment, and have a more favorable prognosis [6,7]. While representing only ~15% of all clinical cases Type II disease is responsible for around ~48% of endometrial cancerrelated deaths, despite adjuvant chemotherapy and radiation, mainly due to metastasis and recurrent disease [7].
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