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
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/un
cleaved 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.
1. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17(7):395-417.
2. Kim J, Gosnell JE, Roman SA. Geographic influences in the global rise of thyroid cancer. Nat Rev Endocrinol. 2020;16(1):17-29.
3. Seo H, Li HY, Perez-Reyes E, Lee J-H. Effects of eugenol on T-type Ca2+ channel isoforms. J Pharmacol Exp Ther. 2013;347(2):310-7.
4. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1-133.
5. Nguyen QT, Lee EJ, Huang MG, Park YI, Khullar A, Plodkowski RA. Diagnosis and treatment of patients with thyroid cancer. Am Health Drug Benefits. 2015;8(1):30.
6. Montor WR, Salas AROSE, de Melo FHM. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol Cancer. 2018;17(1):1-18.
7. Thomas L, Lai SY, Dong W, Feng L, Dadu R, Regone RM, et al. Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist. 2014;19(3):251.
8. Leary M, Heerboth S, Lapinska K, Sarkar S. Sensitization of drug resistant cancer cells: a matter of combination therapy. Cancers. 2018;10(12):483.
9. Yin S-Y, Wei W-C, Jian F-Y, Yang N-S. Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Alternat Med. 2013;2013.
10. Nejad SM, Özgüneş H, Başaran N. Pharmacological and toxicological properties of eugenol. Turkish J Pharm Sci. 2017;14(2):201.
11. Jaganathan SK, Supriyanto E. Antiproliferative and molecular mechanism of eugenol-induced apoptosis in cancer cells. Molecules. 2012;17(6):6290-304.
12. Al-Sharif I, Remmal A, Aboussekhra A. Eugenol triggers apoptosis in breast cancer cells through E2F1/survivin down-regulation. BMC Cancer. 2013;13(1):1-10.
13. Yoo CB, Han KT, Cho KS, Ha J, Park HJ, Nam JH, et al. Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells. Cancer Lett. 2005;225(1):41-52.
14. Varadarajan S, Narasimhan M, Balaji TM, Chamundeeswari DP, Sakthisekaran D. In vitro anticancer effects of cinnamomum verum J. Presl, Cinnamaldehyde, 4 Hydroxycinnamic acid and Eugenol on an oral squamous cell carcinoma cell line. J Contemp Dent Pract. 2020;21:1027-33.
15. Maghbool M, Khosravi T, Vojdani S, Chaijan MR, Esmaeili F, Amani A, et al. The effects of eugenol nanoemulsion on pain caused by arteriovenous fistula cannulation in hemodialysis patients: A randomized double-blinded controlled cross-over trial. Complement Ther Med. 2020;52:102440.
16. Benencia F, Courreges M. In vitro and in vivo activity of eugenol on human herpesvirus. Phytother Res. 2000;14(7):495-500.
17. Gülçin İ. Antioxidant activity of eugenol: A structure–activity relationship study. J Med Food. 2011;14(9):975-85.
18. Barboza JN, da Silva Maia Bezerra Filho C, Silva RO, Medeiros JVR, de Sousa DP. An overview on the anti-inflammatory potential and antioxidant profile of eugenol. Oxid Med Cell Longev. 2018;2018.
19. Fathy M, Fawzy MA, Hintzsche H, Nikaido T, Dandekar T, Othman EM. Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation. Molecules. 2019;24(21):3979.
20. Chou T-C. Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacol Rev. 2006;58(3):621-81.
21. Cervello M, Bachvarov D, Lampiasi N, Cusimano A, Azzolina A, McCubrey JA, et al. Novel combination of sorafenib and celecoxib provides synergistic anti-proliferative and pro-apoptotic effects in human liver cancer cells. PloS One. 2013;8(6):e65569.
22. Tomonari T, Takeishi S, Taniguchi T, Tanaka T, Tanaka H, Fujimoto S, et al. MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma. Oncotarget. 2016;7(6):7207.
23. Fujisawa S, Atsumi T, Kadoma Y, Sakagami H. Antioxidant and prooxidant action of eugenol-related compounds and their cytotoxicity. Toxicology. 2002;177(1):39-54.
24. Chung G, Im S, Kim Y, Jung S, Rhyu M-R, Oh S. Activation of transient receptor potential ankyrin 1 by eugenol. Neuroscience. 2014;261:153-60.
25. de Sa Junior PL, Câmara DAD, Costa AS, Ruiz JLM, Levy D, Azevedo RA, et al. Apoptotic effect of eugenol envolves G2/M phase abrogation accompanied by mitochondrial damage and clastogenic effect on cancer cell in vitro. Phytomedicine. 2016;23(7):725-35.
26. Shi Y, Mo X, Hong S, Li T, Chen B, Chen G. Studying the role and molecular mechanisms of MAP4K3 in sorafenib resistance of hepatocellular carcinoma. Biomed Res Int. 2020;2020.
27. Bonelli MA, Fumarola C, Alfieri RR, La Monica S, Cavazzoni A, Galetti M, et al. Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010;124(1):79-88.
28. Liang W-Z, Chou C-T, Hsu S-S, Liao W-C, Shieh P, Kuo D-H, et al. The involvement of mitochondrial apoptotic pathway in eugenol-induced cell death in human glioblastoma cells. Toxicol Lett. 2015;232(1):122-32.
29. Sarkar A, Bhattacharjee S, Mandal DP. Induction of apoptosis by eugenol and capsaicin in human gastric cancer AGS cells-elucidating the role of p53. Asian Pac J Cancer Prev. 2015;16(15):6753-9.
30. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51(1):27-41.
31. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516.
32. Jiang S, Wang Q, Feng M, Li J, Guan Z, An D, et al. C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells. Appl Microbiol Biotechnol. 2017;101(4):1535-46.
33. Yao X, Zhao C-r, Yin H, Wang K, Gao J-j. Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells. Acta Pharmacol Sin. 2020;41(12):1609-20.
34. Guney Eskiler G, Deveci AO, Bilir C, Kaleli S. Synergistic effects of nobiletin and sorafenib combination on metastatic prostate cancer cells. Nutr Cancer. 2019;71(8):1299-312.
35. Yi J-L, Shi S, Shen Y-L, Wang L, Chen H-Y, Zhu J, et al. Myricetin and methyl eugenol combination enhances the anticancer activity, cell cycle arrest and apoptosis induction of cis-platin against HeLa cervical cancer cell lines. Int J Clin Exp Pathol. 2015;8(2):1116.
2. Kim J, Gosnell JE, Roman SA. Geographic influences in the global rise of thyroid cancer. Nat Rev Endocrinol. 2020;16(1):17-29.
3. Seo H, Li HY, Perez-Reyes E, Lee J-H. Effects of eugenol on T-type Ca2+ channel isoforms. J Pharmacol Exp Ther. 2013;347(2):310-7.
4. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1-133.
5. Nguyen QT, Lee EJ, Huang MG, Park YI, Khullar A, Plodkowski RA. Diagnosis and treatment of patients with thyroid cancer. Am Health Drug Benefits. 2015;8(1):30.
6. Montor WR, Salas AROSE, de Melo FHM. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol Cancer. 2018;17(1):1-18.
7. Thomas L, Lai SY, Dong W, Feng L, Dadu R, Regone RM, et al. Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist. 2014;19(3):251.
8. Leary M, Heerboth S, Lapinska K, Sarkar S. Sensitization of drug resistant cancer cells: a matter of combination therapy. Cancers. 2018;10(12):483.
9. Yin S-Y, Wei W-C, Jian F-Y, Yang N-S. Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Alternat Med. 2013;2013.
10. Nejad SM, Özgüneş H, Başaran N. Pharmacological and toxicological properties of eugenol. Turkish J Pharm Sci. 2017;14(2):201.
11. Jaganathan SK, Supriyanto E. Antiproliferative and molecular mechanism of eugenol-induced apoptosis in cancer cells. Molecules. 2012;17(6):6290-304.
12. Al-Sharif I, Remmal A, Aboussekhra A. Eugenol triggers apoptosis in breast cancer cells through E2F1/survivin down-regulation. BMC Cancer. 2013;13(1):1-10.
13. Yoo CB, Han KT, Cho KS, Ha J, Park HJ, Nam JH, et al. Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells. Cancer Lett. 2005;225(1):41-52.
14. Varadarajan S, Narasimhan M, Balaji TM, Chamundeeswari DP, Sakthisekaran D. In vitro anticancer effects of cinnamomum verum J. Presl, Cinnamaldehyde, 4 Hydroxycinnamic acid and Eugenol on an oral squamous cell carcinoma cell line. J Contemp Dent Pract. 2020;21:1027-33.
15. Maghbool M, Khosravi T, Vojdani S, Chaijan MR, Esmaeili F, Amani A, et al. The effects of eugenol nanoemulsion on pain caused by arteriovenous fistula cannulation in hemodialysis patients: A randomized double-blinded controlled cross-over trial. Complement Ther Med. 2020;52:102440.
16. Benencia F, Courreges M. In vitro and in vivo activity of eugenol on human herpesvirus. Phytother Res. 2000;14(7):495-500.
17. Gülçin İ. Antioxidant activity of eugenol: A structure–activity relationship study. J Med Food. 2011;14(9):975-85.
18. Barboza JN, da Silva Maia Bezerra Filho C, Silva RO, Medeiros JVR, de Sousa DP. An overview on the anti-inflammatory potential and antioxidant profile of eugenol. Oxid Med Cell Longev. 2018;2018.
19. Fathy M, Fawzy MA, Hintzsche H, Nikaido T, Dandekar T, Othman EM. Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation. Molecules. 2019;24(21):3979.
20. Chou T-C. Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacol Rev. 2006;58(3):621-81.
21. Cervello M, Bachvarov D, Lampiasi N, Cusimano A, Azzolina A, McCubrey JA, et al. Novel combination of sorafenib and celecoxib provides synergistic anti-proliferative and pro-apoptotic effects in human liver cancer cells. PloS One. 2013;8(6):e65569.
22. Tomonari T, Takeishi S, Taniguchi T, Tanaka T, Tanaka H, Fujimoto S, et al. MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma. Oncotarget. 2016;7(6):7207.
23. Fujisawa S, Atsumi T, Kadoma Y, Sakagami H. Antioxidant and prooxidant action of eugenol-related compounds and their cytotoxicity. Toxicology. 2002;177(1):39-54.
24. Chung G, Im S, Kim Y, Jung S, Rhyu M-R, Oh S. Activation of transient receptor potential ankyrin 1 by eugenol. Neuroscience. 2014;261:153-60.
25. de Sa Junior PL, Câmara DAD, Costa AS, Ruiz JLM, Levy D, Azevedo RA, et al. Apoptotic effect of eugenol envolves G2/M phase abrogation accompanied by mitochondrial damage and clastogenic effect on cancer cell in vitro. Phytomedicine. 2016;23(7):725-35.
26. Shi Y, Mo X, Hong S, Li T, Chen B, Chen G. Studying the role and molecular mechanisms of MAP4K3 in sorafenib resistance of hepatocellular carcinoma. Biomed Res Int. 2020;2020.
27. Bonelli MA, Fumarola C, Alfieri RR, La Monica S, Cavazzoni A, Galetti M, et al. Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010;124(1):79-88.
28. Liang W-Z, Chou C-T, Hsu S-S, Liao W-C, Shieh P, Kuo D-H, et al. The involvement of mitochondrial apoptotic pathway in eugenol-induced cell death in human glioblastoma cells. Toxicol Lett. 2015;232(1):122-32.
29. Sarkar A, Bhattacharjee S, Mandal DP. Induction of apoptosis by eugenol and capsaicin in human gastric cancer AGS cells-elucidating the role of p53. Asian Pac J Cancer Prev. 2015;16(15):6753-9.
30. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51(1):27-41.
31. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516.
32. Jiang S, Wang Q, Feng M, Li J, Guan Z, An D, et al. C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells. Appl Microbiol Biotechnol. 2017;101(4):1535-46.
33. Yao X, Zhao C-r, Yin H, Wang K, Gao J-j. Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells. Acta Pharmacol Sin. 2020;41(12):1609-20.
34. Guney Eskiler G, Deveci AO, Bilir C, Kaleli S. Synergistic effects of nobiletin and sorafenib combination on metastatic prostate cancer cells. Nutr Cancer. 2019;71(8):1299-312.
35. Yi J-L, Shi S, Shen Y-L, Wang L, Chen H-Y, Zhu J, et al. Myricetin and methyl eugenol combination enhances the anticancer activity, cell cycle arrest and apoptosis induction of cis-platin against HeLa cervical cancer cell lines. Int J Clin Exp Pathol. 2015;8(2):1116.
| Files | ||
| Issue | Vol 21 No 3 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i3.9804 | |
| Keywords | ||
| Apoptosis Drug synergism Eugenol Sorafenib Thyroid neoplasms | ||
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How to Cite
1.
Talezadeh Shirazi P, Farjadian S, Dabbaghmanesh MH, Jonaidi H, Alavianmehr A, Kalani M, Emadi L. Eugenol: A New Option in Combination Therapy with Sorafenib for the Treatment of Undifferentiated Thyroid Cancer. Iran J Allergy Asthma Immunol. 2022;21(3):313-321.
