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Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo

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ABSTRACT

Purpose

The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC.

Methods

Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model.

Results

There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ’s ability to inhibit EC tumor growth and progression without significant toxicity.

Conclusions

IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations.

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Abbreviations

BAX:

Bcl-2-associated X protein gene

Bcl-2:

B-cell lymphoma/leukemia-2 gen

Bcl-xL:

Bcl-2 homologue B-cell lymphoma-extra large

E2:

Estrogen

EC:

Endometrial cancer

EH:

Endometrial hyperplasia

ER:

Estrogen receptors

GnRH:

Gonadotropin-releasing hormone

IQ:

Imiquimod

Mcl-1:

Myeloid cell leukemia 1

MAPK:

Mitogen-activated protein kinas

PARP:

Poly (ADP-ribose) polymerase

P4:

Progesterone

TLR:

Toll-like receptors

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported in part by a Faculty and Creative Grant and Department of Obstetrics and Gynecology at the University of Utah, National Cancer Institute under award number R01-CA140348-01, and The Huntsman Cancer Institute’s Women’s Disease-Oriented Teams Research Funding. We would like to thank Dr. Victoria Bae-Jump, University of North Carolina at Chapel Hill for providing Ishikawa cells, Chieh-Hsiang Yang, Jesus Arellano, and Cameron Neilson for assisting with animal studies and data collection, and Benjamin J. Bruno, Dr. Andrew Dixon, and Dr. Sebastien Taurin for scientific discussions and help with data analyses.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah, Salt Lake City, UT, 84132, USA

    Aliyah Almomen, Elke A. Jarboe, Mark K. Dodson, C. Matthew Peterson & Margit M. Janát-Amsbury

  2. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA

    Aliyah Almomen, Shawn C. Owen & Margit M. Janát-Amsbury

  3. Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA

    Elke A. Jarboe

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  1. Aliyah Almomen
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Correspondence to Margit M. Janát-Amsbury.

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Almomen, A., Jarboe, E.A., Dodson, M.K. et al. Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo . Pharm Res 33, 2209–2217 (2016). https://doi.org/10.1007/s11095-016-1957-6

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