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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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