Synergistic effects of Ferula gummosa and radiotherapy on induction of cytotoxicity in HeLa cell line

Document Type: Original Research Article


1 Department of Biochemistry and Biophysics, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran

2 Department of Pharmacology and Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

4 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran


Objective: Cervical cancer is the second most common type of cancer among women, worldwide; and for treatment of this type of cancer radiotherapy is commonly used. Ferula gummosa Boiss(“Barije” in Persian, from the family Apiaceae), (F. gummosa), is an extremely precious medicinal plant which naturally grows throughout the Mediterranean and Central Asia and is a native plant in Iran. The present study examined the cytotoxic effects of F. gummosa in terms of induction of apoptosis and radiosensitivity in HeLa cells.
Materials and Methods: In order to determine F. gummosa cytotoxicity in HeLa cells, the cells were incubated with different concentrations of the plant resin(0-1000 µg/ml) for 24, 48 and 72 hr. Cytotoxicity was determined by MTT assay. The role of apoptosis in F. gummosa cytotoxicity was investigated using flow cytometry following propidium iodide (PI) staining of DNA. For radiosensitivity assessment, F. gummosa-treated cells were exposed to 2 Gy γ-rays, and cytotoxicity was determined in irradiated and non-irradiated (control) groups by MTT and the synergism factor was calculated.
Results: F. gummosa decreased cell viability in HeLa cells in a concentration- and time-dependent manner. Flow cytometryanalysisindicated that apoptosis is involved in F. gummosa-induced cytotoxicity. Co-administration of F. gummosa and radiotherapy, showed that this plantat non-toxic low doses, could result in almost 5-fold increment in sensitization of cells towards radiation-induced toxicity.
Conclusion: The concurrent use of F. gummosa and radiation increases radiosensitivity and cell death. Therefore, F. gummosa can be considered as a potential radiosensitizer agent against cervical cancer.


Main Subjects

Ashkenazi A, Dixit VM. 1998. Death receptors: signaling and modulation. Science, 281: 1305-1308.

Britten RA, Evans  AJ, Allalunis-Turner  MJ, Pearcey  RG. 1996. Effect of cisplatin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines. Int J Radiat Oncol Biol Phys, 34: 367-374.

Dayal R, Singh A, Pandey A, Mishra KP. 2014. Reactive oxygen species as mediator of tumor radiosensitivity. J Cancer Res Ther, 10: 811.

Debatin K-M, Poncet D Kroemer, G. 2002. Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene, 21: 8786-8803.

Elmore, S. 2007. Apoptosis: a review of programmed cell death. Toxicol Pathol, 35: 495-516.

Foucquier J, Guedj  M. 2015. Analysis of drug combinations: current methodological landscape. Pharmacol Res Perspect, 3:e00149.

Gharaei R, Ghobadi S, Akrami H. 2011. Study of apoptosis inducing effects of ethanol extract of Ferula gummosa leaf. Clin. Biochem., 44: S332.

Gharaei R, Akrami H, Heidari S, Asadi MH, Jalili A. 2013. The suppression effect of Ferula gummosa Boiss. Extracts on cell proliferation through apoptosis induction in gastric cancer cell line. Eur J Integr Med, 5:241-7

Ghorbani A, Mohebbati R, Jafarian AH, Vahedi MM, Hosseini SM, Soukhtanloo M, Sadeghnia HR, Hosseini A. 2016. Toxicity evaluation of hydroalcoholic extract of Ferula gummosa root. Regul Toxicol Pharmacol, 77:35-41.

Gordon Steel G, Peckham MJ. 1979. Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys, 5: 85-91.

Green DR, Reed JC. 1998. Mitochondria and apoptosis. Science-AAAS-Weekly Paper Edition, 281: 1309-1311.

Gudarzi H, Salimi M, Irian S, Amanzadeh A, Mostafapour Kandelous H, Azadmanesh  K, Salimi M. 2015. Ethanolic extract of Ferula gummosa is cytotoxic against cancer cells by inducing apoptosis and cell cycle arrest. Nat Prod Res, 29:546-550.

Hersey P, Zhang XD. 2001. How melanoma cells evade trail-induced apoptosis. Nat. Rev. Cancer., 1: 142-150.

Hosseini A, Javadi SS, Fani-Pakdel A, Mousavi SH.  2017. Kelussia odoratissimapotentiates cytotoxic effects of radiation in HeLa cancer cell line. Avecina J Phytomed, 7:137-144.

Iranshahi, M, Rezaee R, Najaf Najafi M, Haghbin A, Kasaian J.  2018. Cytotoxic activity of the genus Ferula (Apiaceae) and its bioactive constituents. Avecina J Phytomed, Epub ahead of print.

Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26: 239-257.

Luo J, Zhu W, Tang  Y, Cao H, Zhou Y, Ji R, Zhou X, Lu Z, Yang H, Zhang S, Cao J. 2014. Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo. Radiat Oncol, 9:84.

Magne N, Fischel J, Dubreuil A, Formento P, Marcie S, Lagrange J, Milano G. 2002. Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer. Br J Cancer, 86: 819-827.

Moody CA, Laimins LA. 2010. Human papillomavirus oncoproteins: pathways to transformation. Nat. Rev. Cancer., 10: 550-560.

Moosavi SJ, Habibian M, Peeri M, Azarbayjani MA, Nabavi SM, Nabavi SF, et al. 2014. Protective effect of Ferula gummosa hydroalcoholic extract against nitric oxide deficiency-induced oxidative stress and inflammation in rats renal tissues. CLIN EXP HYPERTENS.,37:136-141.

Mortazaienezhad F, Sadeghian M. 2006. Investigation of Compounds from Galbanum (Ferula gummosa) Boiss. Asian Journal of Plant Sciences, 5:905-906.Mosmann T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65: 55-63.

Mousavi SH, Moallem SA, Mehri S, Shahsavand S, Nassirli H, Malaekeh-Nikouei B. 2011. Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form. Pharm Biol, 49: 1039-1045.

Mousavi SH, Tavakkol-Afshari J, Brook A, Jafari-Anarkooli I. 2009. Direct toxicity of Rose Bengal in MCF-7 cell line: role of apoptosis. Food Chem Toxicol, 47: 855-859.

Mousavi SH, Tayarani NZ, Hersey P. 2008. Apoptosis: from signalling pathways to therapeutic tools. Iran J Basic Med Sci, 11:121-142.

Nabavi SF, Habtemariam S, Sureda A, Nabavi, SM. 2012. Ferula gummosa boiss as a rich source of natural antioxidants with numerous therapeutic uses-a short review. Medicinal Plants as Antioxidant Agents: Understanding Their Mechanism of Action and Therapeutic Efficacy: Research Signpost, 2012: 15-26.

Okada H, Mak TW. 2004. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat. Rev. Cancer, 4: 592-603.

Ouyang L, Luo Y, Tian M, Zhang SY, Lu R, Wang JH, et al. 2014. Plant natural products: from traditional compounds to new emerging drugs in cancer therapy. CELL PROLIFERAT., 47: 506-515.

Rose PG, Bundy BN, Watkins EB, Thigpen  JT, Deppe G, Maiman MA, et al. 1999. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med, 340: 1144-1153.

Schiffman M, Castle PE. 2005. The promise of global cervical-cancer prevention. N Engl J Med, 353: 2101-2104.

Scorrano L, Oakes SA, Opferman JT, Cheng  EH, Sorcinelli MD, Pozzan T, et al. 2003. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 300: 135-139.

Tayarani-Najaran Z, Mousavi SH, Asili J, Emami SA. 2010. Growth-inhibitory effect of Scutellaria lindbergii in human cancer cell lines. Food Chem Toxicol, 48: 599-604.

Tayarani-Najarani Z, Asili J, Parsaee H, Mousavi SH, Mashhadian NV, Mirzaee A, et al. 2012. Wogonin and neobaicalein from Scutellaria litwinowii roots are apoptotic for HeLa cells. Rev. bras. farmacogn., 22: 268-276.

Waggoner SE. 2003. Cervical cancer. The Lancet, 361: 2217-2225.

Yang L-L, Wang B-Q, Chen L-L, Luo H-Q, Wu J-B. 2012. CXCL10 enhances radiotherapy effects in HeLa cells through cell cycle redistribution. Oncol Lett, 3: 383-386.

Zhang XD, Gillespie SK, Hersey P. 2004. Staurosporine induces apoptosis of melanoma by both caspase-dependent and-independent apoptotic pathways. Mol Cancer Ther, 3: 187-197.