Eugenol: A New Option in Combination Therapy with Sorafenib  for the Treatment of Undifferentiated Thyroid Cancer

Pedram Talezadeh Shirazi; Shirin Farjadian; Mohammad Hossein  Dabbaghmanesh; Hossein Jonaidi; Ali Alavianmehr; Mehdi Kalani; Ladan Emadi

doi:10.18502/ijaai.v21i3.9804

Pedram Talezadeh Shirazi Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar, University of Kerman, Kerman, Iran
Shirin Farjadian Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
Mohammad Hossein Dabbaghmanesh Shiraz Endocrine and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Hossein Jonaidi Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar, University of Kerman, Kerman, Iran
Ali Alavianmehr Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
Mehdi Kalani Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Ladan Emadi Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar, University of Kerman, Kerman, Iran

DOI: https://doi.org/10.18502/ijaai.v21i3.9804

Keywords: Apoptosis; Drug synergism; Eugenol; Sorafenib; Thyroid neoplasms

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy. Thyroidectomy and radiotherapy are common treatment modalities for patients with undifferentiated TC (UTC), and sorafenib is usually recommended to prevent a recurrence. However, malignant cells may evade chemotherapy-induced apoptosis, and combination therapy was developed to achieve better outcomes. This study investigated whether eugenol in combination with sorafenib was more effective than either substance individually in triggering apoptosis in the UTC.

The IC₅₀ of sorafenib and eugenol was determined in a UTC cell line (8305C) by MTT assay, and their synergistic effect in combination therapy was investigated. Flow cytometry was used to evaluate the rate of apoptosis in treated cells. To confirm that cell death occurred through apoptosis, immunoblotting was used to determine the relative cleavage of caspase-8 and caspase-9.

The IC₅₀ of sorafenib was 20 µM, and that of eugenol was 2100 µM. The sorafenib-eugenol combination (1:105) showed synergistic effects at concentrations equal to or less than their IC₅₀. The rate of apoptosis induction was higher in cells treated with eugenol or the eugenol-sorafenib combination compared to sorafenib-treated cells. The relative intensity of cleaved/uncleaved forms of caspase-8 increased in eugenol-treated cells compared to sorafenib-treated cells.

Sorafenib and eugenol at concentrations equal to or less than their IC₅₀ had a synergistic effect in 8305C cells. The most potent apoptotic effect was achieved with sorafenib and eugenol at their IC₅₀. Lower doses of sorafenib could be used with eugenol to improve its efficacy while reducing its side effects.