Oncotarget

Research Papers:

Treatment with epigenetic agents profoundly inhibits tumor growth in leiomyosarcoma

Cynthia De Carvalho Fischer, Yue Hu, Michael Morreale, Wan Ying Lin, Akhil Wali, Maya Thakar, Enusha Karunasena, Rupashree Sen, Yi Cai, Lauren Murphy, Cynthia A. Zahnow, Harold Keer, Manjusha Thakar and Nita Ahuja _

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Oncotarget. 2018; 9:19379-19395. https://doi.org/10.18632/oncotarget.25056

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Abstract

Cynthia De Carvalho Fischer1,2, Yue Hu1,3, Michael Morreale1, Wan Ying Lin1, Akhil Wali1, Maya Thakar1, Enusha Karunasena4, Rupashree Sen4, Yi Cai4, Lauren Murphy4, Cynthia A. Zahnow4, Harold Keer5, Manjusha Thakar1 and Nita Ahuja1,4,6

1Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States

2Institut für Allgemein, Viszeral und Transplantationschirurgie, Charite Universitätsmedizin Berlin, Berlin, Germany

3Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China

4Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

5Astex Pharmaceuticals Inc., Pleasanton, CA, United States

6Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Correspondence to:

Nita Ahuja, email: nita.ahuja@yale.edu

Manjusha Thakar, email: mthakar3@jhmi.edu

Keywords: leiomyosarcoma; 5-azacitidine; Guadecitabine

Abbreviations: LMS: leiomyosarcoma; Aza: 5-azacitidine; DAC: Decitabine; SGI-110: Guadecitabine

Received: November 06, 2017     Accepted: March 15, 2018     Published: April 10, 2018

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.


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