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Oncotarget. 2018 Apr 10;9(27):19379-19395. doi: 10.18632/oncotarget.25056. eCollection 2018 Apr 10.

Treatment with epigenetic agents profoundly inhibits tumor growth in leiomyosarcoma.

Author information

1
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
2
Institut für Allgemein, Viszeral und Transplantationschirurgie, Charite Universitätsmedizin Berlin, Berlin, Germany.
3
Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
4
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
5
Astex Pharmaceuticals Inc., Pleasanton, CA, United States.
6
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Abstract

Leiomyosarcomas are rare mesenchymal neoplasms characterized by a smooth muscle differentiation pattern. Due to the extremely poor prognosis in patients, the development of novel chemotherapeutic regimens remains critically important. In this study, multiple leiomyosarcoma cell lines, SK-UT1, SK-LMS1, and MES-SA were treated with varying doses of the DNA Methyltransferase Inhibitors (DNMTi) 5-azacitidine (Aza), 5-aza-2-deoxycytidine (DAC), and guadecitabine (SGI-110). The effect of these epigenetic modulators was measured using both in-vitro and in-vivo models. Of the three epigenetic modulators, Guadecitabine was the most effective at decreasing cell survival in LMS cell lines. SK-UT1 was found to be the more sensitive to all three epigenetic modulators, while SK-LMS1 and MES-SA were more resistant. The contrast in sensitivity seen was also represented by the increase in apoptosis in Aza and guadecitabine. In parallel with Aza, guadecitabine was observed to also arrest the cell cycle. Treatment with guadecitabine led to a decrease in growth across the spectrum of sensitivity in LMS cell lines, both in a delayed in vitro and in vivo model; in parallel experiments, apoptotic pathways were activated in sensitive and less sensitive lines. Additional studies are required to explore potential therapeutic applications and mechanisms for leiomyosarcoma treatment.

KEYWORDS:

5-azacitidine; Guadecitabine; leiomyosarcoma

Conflict of interest statement

CONFLICTS OF INTEREST Ahuja has licensed biomarkers for early detection of pancreas cancers to Cepheid, consultant- Celgene, research support–Astex.

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