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Description of the cytotoxic effect of a novel drug Abietyl-Isothiocyanate on endometrial cancer cell lines

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Summary

The objective of the present study was to determine the in-vitro effect of Abietyl-Isothiocyanate (ABITC), a representative of a new class of anti-cancer drugs, on endometrial cancer (EC) cell lines. ABITC at concentrations ≥1 μM displayed dose-dependent and selective cytotoxicity to EC cell lines (ECC-1, AN3CA, RL95-2) in comparison to other cancer cell lines. After treatment with ABITC, ECC-1 unlike control cells displayed hallmark features of apoptosis including chromatin condensation and nuclear fragmentation. At concentrations below the IC50, ABITC exerted anti-proliferative effects by blocking cell-cycle progression through G0/G1 and S-phase. In addition, cells attempted to counteract drug treatment by pro-survival signaling such as deactivation of JNK/SAPK and p38 MAPK and activation of AKT and ErK1/2. ABITC also altered EGF-receptor phosphorylation. At a concentration of 5 μM ABITC generated an excess amount of reactive oxygen species (ROS) and displayed pro-apoptotic signaling such as activation of caspase-8, JNK-SAPK and deactivation of PARP-1. Co-treatment with an antioxidant blocked the drug effects by reducing ROS generation, cytotoxicity and pro-apoptotic signaling. In summary, novel isothiocyanate ABITC is an anti-proliferative and selectively cytotoxic drug to EC cells in-vitro. Key mechanisms during cell death are predominantly correlated to excess generation of ROS. We suggest the further development of ABITC as a potential therapeutic by studying the drug efficacy in EC in-vivo models.

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Abbreviations

EC:

Endometrial cancer

ABITC:

Abietyl-Isothiocyanate

ITC:

Isothiocyanate

ROS:

Reactive oxygen species

MAPK:

Mitogen activated protein kinase

FACS:

Fluorescent activated cell sorting

EGF:

Epidermal growth factor

DAPI:

4′-6-Diamidino-2-Phenylindole

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Acknowledgements

RGM is partially supported by NCI Grant #1 RO1 CA136491-01 and Grants from Swim Across America. The authors thank Dr. R. K. Singh for design of compound Abietyl-Isothiocyanate.

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Authors and Affiliations

  1. Molecular Therapeutics Laboratory, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Alpert Medical School, Brown University, 101 Dudley Street, Providence, RI, 02905, USA

    Timothy C. Horan, Kyu Kwang Kim, Richard G. Moore & Thilo S. Lange

  2. Department of Chemistry, Brown University, Providence, RI, 02912, USA

    Michael A. Zompa & Christopher T. Seto

  3. Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, 02912, USA

    Thilo S. Lange

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  1. Timothy C. Horan
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  2. Michael A. Zompa
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  4. Kyu Kwang Kim
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  5. Richard G. Moore
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  6. Thilo S. Lange
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Correspondence to Thilo S. Lange.

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Horan, T.C., Zompa, M.A., Seto, C.T. et al. Description of the cytotoxic effect of a novel drug Abietyl-Isothiocyanate on endometrial cancer cell lines. Invest New Drugs 30, 1460–1470 (2012). https://doi.org/10.1007/s10637-011-9728-z

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  • DOI: https://doi.org/10.1007/s10637-011-9728-z

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