Cytotoxic activity of the genus Ferula (Apiaceae) and its bioactive constituents

Document Type : Review Article


1 Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran


Objective: The genus Ferula L. includes perennial flowering plants belonging to the Apiaceae family. This genus is a rich source of biologically active phytochemicals such as sulfur-containing derivatives, coumarins, sesquiterpenes, sesquiterpene lactones, sesquiterpene coumarins, glucuronic acid, galactose, arabinose, rhamnose, and daucane esters. Over the last decade, considerable attention has been paid to biological activities of these compounds; it is assumed that the most prominent biological features of the genus Ferula are their cytotoxic effects. This article discusses cytotoxic activity of the genus Ferula and their important compounds.
Methods: In this mini-review article, papers published from 1990 to April 2016 were included and the following information was discussed; cytotoxic activity of the genus Ferula and their important compounds, the type of cell line used in vitro, concentrations of the extracts/active compound that were used, and the underlying mechanisms of action through which Ferula-related chemicals induced cytotoxicity. In addition, we explained different mechanisms of action through which the active constituents isolated from Ferula, could decrease cellular growth.
Conclusion: It is highly recommended that potent and effective compounds that were isolated from Ferula plants and found to be appropriate as adjuvant therapy for certain diseases, should be identified. Also, the versatile biological activities of sesquiterpene coumarins suggest them as promising agents with a broad range of biological applications to be used in the future.


Main Subjects

Aas Z, Babaei E, Feizi MAH, Dehghan G. 2015. Anti-proliferative and apoptotic effects of dendrosomal farnesiferol c on gastric cancer cells. Asian Pac J Cancer Prev, 16:5325-5329.
Alam M, Khan A, Wadood A, Khan A, Bashir S, Aman A, Jan AK, Rauf A, Ahmad B, Khan AR. 2016. Bioassay-guided isolation of sesquiterpene coumarins from Ferula narthex Bioss: A new anticancer agent. Front pharmacol, 7: 26-40.
Aldaghi L, Rad A, Arab A, Kasaian J, Iranshahi M, Sadr A, Soltani F. 2016. In silico and in vitro evaluation of cytotoxic activities of farnesiferol c and microlobin on MCF-7, HeLa and KYSE Cell Lines. Drug Res, 66: 532–538.
Altmann K-H, Gertsch J. 2007. Anticancer drugs from nature—natural products as a unique source of new microtubule-stabilizing agents. Nat Prod Rep, 24:327-357.
Appendino G, Maxia L, Bascope M, Houghton PJ, Sanchez-Duffhues G, Muñoz E, Sterner O. 2006. A meroterpenoid NF-κB inhibitor and drimane sesquiterpenoids from asafetida. J Nat Prod, 69:1101-1104.
Arghiani N, Matin MM, Bahrami AR, Iranshahi M, Sazgarnia A, Rassouli FB. 2014. Investigating anticancer properties of the sesquiterpene ferutinin on colon carcinoma cells, in vitro and in vivo. Life Sci, 109:87-94.
Asadi-Samani M, Kooti W, Aslani E, Shirzad H. 2015. A systematic review of iran’s medicinal plants with anticancer effects. J Evid Based Complement Alternat Med. 21: 143-153.
Asghari J, Atabaki V, Baher E, Mazaheritehrani M. 2016. Identification of sesquiterpene coumarins of oleo-gum resin of Ferula assa-foetida L. from the Yasuj region. Nat Prod Res, 30:350-353.
Bagheri SM, Sahebkar A, Gohari AR, Saeidnia S, Malmir M, Iranshahi M. 2010. Evaluation of cytotoxicity and anticonvulsant activity of some Iranian medicinal Ferula species. Pharm Biol, 48:242-246.
Bansal P, Gupta V V, Bansal R, Sapra R. 2012. Dietary phytochemicals in cell cycle arrest and apoptosis-an insight. J Drug Deliv Ther, 2(2): 8-17.
Barthomeuf C, Demeule M, Grassi J, Saidkhodjaev A, Beliveau R. 2006. Conferone from Ferula schtschurowskiana enhances vinblastine cytotoxicity in MDCK-MDR1 cells by competitively inhibiting P-glycoprotein transport. Planta Med, 72:634-639.
Barthomeuf C, Lim S, Iranshahi M, Chollet P. 2008. Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine, 15:103-111.
Behnam Rassouli F, Matin MM, Iranshahi M, Bahrami AR, Neshati V, Mollazadeh S, Neshati Z. 2009. Mogoltacin enhances vincristine cytotoxicity in human transitional cell carcinoma (TCC) cell line. Phytomedicine,16:181-187.
Bocca C, Gabriel L, Bozzo F, Miglietta A. 2002. Microtubule-interacting activity and cytotoxicity of the prenylated coumarin ferulenol. Planta Med, 68:1135-1137.
Cha M-R, Choi YH, Choi CW, Kim YS, Kim Y-K, Ryu SY, Choi SU. 2011. Galbanic acid, a cytotoxic sesquiterpene from the gum resin of Ferula asafoetida, blocks protein farnesyltransferase. Planta Med, 77:52-54.
Cheraghi O, Dehghan G, Mahdavi M, Rahbarghazi R, Rezabakhsh A, Charoudeh HN, Iranshahi M, Montazersaheb S. 2016. Potent anti-angiogenic and cytotoxic effect of conferone on human colorectal adenocarcinoma HT-29 cells. Phytomedicine, 23:398-405.
Chitsazian-Yazdi M, Agnolet S, Lorenz S, Schneider B, Es'Haghi Z, Kasaian J, Khameneh B, Iranshahi M. 2015. Foetithiophenes C-F, thiophene derivatives from the roots of Ferula foetida. Pharm Biol, 53:710-714.
Dastan D, Salehi P, Aliahmadi A, Gohari AR, Maroofi H, Ardalan A. 2016. New coumarin derivatives from Ferula pseudalliacea with antibacterial activity. Nat Prod Res, 30:2747-2753.
Dastan D, Salehi P, Ghanati F, Gohari AR, Maroofi H, Alnajar N. 2014a. Phytotoxicity and cytotoxicity of disesquiterpene and sesquiterpene coumarins from Ferula pseudalliacea. Ind Crops Prod, 55:43-48.
Dastan D, Salehi P, Gohari AR, Ebrahimi SN, Aliahmadi A, Hamburger M. 2014b. Bioactive Sesquiterpene Coumarins from Ferula pseudalliacea. Planta Med,. 80:1118-1123.
Elouzi AA, Auzi AA, El-Hammadi M, Gray AI. 2008. Cytotoxicity study of Ferula hermonis boiss. Bull Pharm Sci,. 31:313-317.
Eskandani M, Barar J, Dolatabadi JEN, Hamishehkar H, Nazemiyeh H. 2015. Formulation, characterization, and geno/cytotoxicity studies of galbanic acid-loaded solid lipid nanoparticles. Pharm Biol, 53:1525-1538.
Eslami JB, Dehpouri A, Nemati F, Rezaei B. 2013. Cytotoxicity effects of the Ferula gummosa extract on the cancer cell line MCF7.J Anim Biol, 5:1-7.
Gamal-Eldeen AM, Hegazy MEF. 2010. A crystal lapiferin derived from Ferula vesceritensis induces apoptosis pathway in MCF-7 breast cancer cells. Natl Prod Res, 24:246-257.
Ghannadi A, Fattahian K, Shokoohinia Y, Behbahani M, Shahnoush A. 2014. Anti-viral evaluation of sesquiterpene coumarins from Ferula assa-foetida against HSV-1. Iran J Pharm Res, 13:523-530.
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, 5:241-247.
Gholami O, Jeddi-Tehrani M, Iranshahi M, Zarnani AH, Ziai SA. 2013. Umbelliprenin from Ferula szowitsiana activates both intrinsic and extrinsic pathways of apoptosis in jurkat T-CLL cell line. Iran J Pharm Res, 12:371-376.
Gholami O, Shamsara J. 2016. Comparison of the cytotoxic effects of umbelliprenin and auraptene. Int J Pharm Pharm Sci, 8:1-4.
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.
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.
Haghighitalab A, Matin MM, Bahrami AR, Iranshahi M, Saeinasab M, Haghighi F. 2014. In vitro investigation of anticancer, cell-cycle-inhibitory, and apoptosis-inducing effects of diversin, a natural prenylated coumarin, on bladder carcinoma cells. Z Naturforsch Bio Sci C, 69:99-109.
Hajimehdipoor H, Esmaeili S, Ramezani A, Anaraki MJ, Mosaddegh M. 2012. The cytotoxic effects of Ferula persica var. Persica and Ferula hezarlalehzarica against HepG2, A549, HT29, MCF7 and MDBK cell lines. Iran J Pharm Sci, 8:113-117.
Hamzeloomoghadam M, Esmaeili S, Fotoohi F, Naghibi F, Pirani A, Hajimehdipoor H. 2013. In vitro evaluation for cytotoxic activity of three Ferula species. Int J Pharm Sci Res,. 4:2673-2676.
Hanafi-Bojd MY, Iranshahi M, Mosaffa F, Tehrani SO, Kalalinia F, Behravan J. 2011. Farnesiferol A from Ferula persica and galbanic acid from Ferula szowitsiana inhibit P-glycoprotein-mediated rhodamine efflux in breast cancer cell lines. Planta Med, 77:1590-1593.
Huang J, Han H-Y, Li G-Y, Wang H-Y, Zhang C, Zhang K, Tan Y, Li P-Y, Wang J-H. 2013. Two new terpenoid benzoates with antitumor activity from the roots of Ferula dissecta.  J Asian Nat Prod Res, 15:1100-1106.
Iranshahi M, Arfa P, Ramezani M, Jaafari MR, Sadeghian H, Bassarello C, Piacente S, Pizza C. 2007. Sesquiterpene coumarins from Ferula szowitsiana and in vitro antileishmanial activity of 7-prenyloxycoumarins against promastigotes. Phytochemistry, 68:554-561.
Iranshahi M, Masullo M, Asili A, Hamedzadeh A, Jahanbin B, Festa M, Capasso A, Piacente S. 2010. Sesquiterpene coumarins from Ferula gumosa. J Nat Prod 73:1958-1962.
Iranshahy M, Iranshahi M. 2011. Traditional uses, phytochemistry and pharmacology of asafoetida (Ferula assa-foetida oleo-gum-resin) — A review. J Ethnopharm, 134:1-10.
Kanani MR, Rahiminejad MR, Sonboli A, Mozaffarian V, Kazempour Osaloo S, Nejad Ebrahimi S. 2011. Chemotaxonomic significance of the essential oils of 18 Ferula species (Apiaceae) from Iran. Chem Biodivers, 8:503-517.
Karimi G, Iranshahi M, Hosseinalizadeh F, Riahi B, Sahebkar A. 2010. Screening of acetylcholinesterase inhibitory activity of terpenoid and coumarin derivatives from the genus Ferula. Pharmacol Online, 1:566-574.
Kasaian J, Iranshahy M, Iranshahi M. 2014. Synthesis, biosynthesis and biological activities of galbanic acid–A review. Pharm Biol, 52:524-531.
Kasaian J, Iranshahy M, Masullo M, Piacente S, Ebrahimi F, Iranshahi M. 2014a. Sesquiterpene lactones from Ferula oopoda and their cytotoxic properties. J Asian Nat Prod Res, 16:248-253.
Kasaian J, Mosaffa F, Behravan J, Masullo M, Piacente S, Ghandadi M, Iranshahi M. 2015. Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins. Fitoterapia, 103:149-154.
Kasaian J, Mosaffa F, Behravan J, Masullo M, Piacente S, Iranshahi M. 2016. Modulation of Multidrug Resistance Protein 2 Efflux in the Cisplatin Resistance Human Ovarian Carcinoma Cells A2780/RCIS by Sesquiterpene Coumarins. Phytother Res, 30:84-89.
Keskin O, Bahar I, Jernigan RL, Beutler JA, Shoemaker RH, Sausville EA, Covell DG. 2000. Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. Anticancer Drug Des, 15:79-98.
Khaghanzadeh N, Mojtahedi Z, Ramezani M, Erfani N, Ghaderi A. 2012. Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells. DARU J Pharm Sci, 20:69-75.
Kim KH, Lee HJ, Jeong SJ, Lee EO, Kim HS, Zhang Y, Ryu SY, Lee MH, Lü J, Kim SH. 2011. Galbanic acid isolated from Ferula assafoetida exerts in vivo anti-tumor activity in association with anti-angiogenesis and anti-proliferation. Pharm Res, 28:597-609.
Lee JH, Choi S, Lee Y, Lee HJ, Kim KH, Ahn KS, Bae H, Lee EO, Ryu SY, Lü J, et al. 2010. Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. Mol Cancer Ther, 9:389-399.
Li G, Li X, Cao L, Zhang L, Shen L, Zhu J, Wang J, Si J. 2015. Sesquiterpene coumarins from seeds of Ferula sinkiangensis. Fitoterapia, 103:222-226.
Lourenco AM, M Ferreira L, S Branco P. 2012. Molecules of natural origin, semi-synthesis and synthesis with anti-inflammatory and anticancer utilities. Curr Pharml Des, 18:3979-4046.
Macho A, Blanco-Molina M, Spagliardi P, Appendino G, Bremner P, Heinrich M, Fiebich BL, Muñoz E. 2004. Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line. Biochem Pharmacol, 68:875-883.
Maggi F, Papa F, Dall’Acqua S, Nicoletti M. 2016. Chemical analysis of essential oils from different parts of Ferula communis L. growing in central Italy. Nat Prod Res, 30:806-813.
Mahendra P, Bisht S. 2012. Ferula asaa-foetida : Traditional uses and pharmacological activity. Pharmacog Rev, 6:141-146.
Matin MM, Nakhaeizadeh H, Bahrami AR, Iranshahi M, Arghiani N, Rassouli FB. 2014. Ferutinin, an apoptosis inducing terpenoid from Ferula ovina. Asian Pac J Cancer Prev, 15:2123-2128.
Mirzaaghaei S, Akrami H, Asadi M, Mahdiuni H. 2014. Ferula gummosa Boiss flower and leaf extracts inhibit angiogenesis in vitro. Ind J Cancer, 51: 615-620.
Miski M. 2013. Biologically Active Sesquiterpenes from the Indigenous Ferula species (Apiaceae) of Turkey. Planta Med, 79:PN32.
Mohd Shafri MA, Yusof FA, Md Zain AZ. 2015. In vitro cytotoxic activity of Ferula assa-foetida on osteosarcoma cell line (Hos crl). J Teknol, 77:7-11.
Mollazadeh S, Matin MM, Bahrami AR, Iranshahi M, Behnam-Rassouli M, Rassouli FB, Neshati V. 2011. Feselol enhances the cytotoxicity and DNA damage induced by cisplatin in 5637 cells. Z Naturforsch C, 66: 555-561.
Mollazadeh S, Matin MM, Iranshahi M, Bahrami AR, Neshati V, Behnam-Rassouli F. 2010. The enhancement of vincristine cytotoxicity by combination with feselol. J Asian Nat Prod Res, 12:569-575.
Mousavi SH, Davari A-S, Iranshahi M, Sabouri-Rad S, Najaran ZT. 2015. Comparative analysis of the cytotoxic effect of 7-prenyloxycoumarin compounds and herniarin on MCF-7 cell line. Avicenna J Phytomed, 5:520-530.
Nazari ZE, Iranshahi M. 2011. Biologically active sesquiterpene coumarins from Ferula species. Phytother Res, 25:315-323.
Neshati V, Matin MM, Bahrami AR, Iranshahi M, Rassouli FB, Saeinasab M. 2012. Increasing the cisplatin cytotoxicity and cisplatin-induced DNA damage by conferone in 5637 cells. Nat Prod Res. 26:1724-1727.
Neshatia V, Matin MM, Iranshahi M, Bahrami AR, Behravan J, Mollazadeh S, Rassouli FB. 2009. Cytotoxicity of vincristine on the 5637 cell line is enhanced by combination with conferone. Z Naturforsch C, 64:317-322.
Oh BS, Shin EA, Jung JH, Jung DB, Kim B, Shim BS, Yazdi MC, Iranshahi M, Kim SH. 2015. Apoptotic effect of galbanic acid via activation of caspases and inhibition of Mcl-1 in H460 non-small lung carcinoma cells. Phytother Res, 29:844-849.
Paydar M, Wong YL, Abdulkarim Moharam B, Movahed E, Fen Wong W, Yeng Looi C. 2013. Pharmacological activities and chemical constituents of Ferula szowitsiana DC. J Med Sci (Faisalabad), 13:236-243.
Ramezani A, Iranshahi M, Hanafi-Bojd MY, Malaekeh-Nikouei B. 2014. Preparation, characterization and cytotoxic effects of nanoliposomes containing umbelliprenin. Intern J Pharm Res. 6:79-84.
Rassouli FB, Matin MM, Iranshahi M, Bahrami AR. 2011. Investigating the cytotoxic and apoptosis inducing effects of monoterpenoid stylosin in vitro. Fitoterapia, 82:742-749.
Rassouli FB, Matin MM, Iranshahi M, Bahrami AR, Behravan J, Mollazadeh S, Neshati V, Kalalinia F. 2011. Investigating the enhancement of cisplatin cytotoxicity on 5637 cells by combination with mogoltacin. Toxicol in Vitro, 25:469-474.
Razavi SM, Janani M. 2015. A new ester coumarin from Ferula Persica wild, indigenous to Iran. Nat Prod Res, 29:717-721.
Razavi SM, Nahar L, Talischi H, Sarker SD. 2016. Ferulone A and ferulone B: two new coumarin esters from Ferula orientalis L. roots. Nat Prod Res, 30:2183-2189.
Ryu S-Y, Lee C-O, Choi S-U, Park S-h, Kim Y-S, Kim S-K, Kim S-K, Kang S-K. 2001. Anticancer composition comprising sesquiterpenes isolated from Resina ferulae. In: Google Patents. Publication number : US 20040043083 A1.
Sadeghizadeh M, Ranjbar B, Damaghi M, Khaki L, Sarbolouki MN, Najafi F, Parsaee S, Ziaee AA, Massumi M, Lubitz W. 2008. Dendrosomes as novel gene portersā€III. J Chem Technol Biotech, 83:912-920.
Sadooghi SD, Nezhad Shahrokh Abadi K, Zafar Balanzhad S. 2013. Investigating the cytotoxic effects of ethanolic extract of Ferula assa-foetida resin on HepG2 cell line. KAUMS J (FEYZ), 17:323-330.
Safi R, Rodriguez F, Hilal G, Diab-Assaf M, Diab Y, El-Sabban M, Najjar F, Delfourne E. 2015. Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues. Chem Biol Drug Des, 87:382-397.
Sahranavard S, Naghibi F, Mosaddegh M, Esmaeili S, Sarkhail P, Taghvaei M, Ghafari S. 2009. Cytotoxic activities of selected medicinal plants from Iran and phytochemical evaluation of the most potent extract. Res Pharm Sci, 4:133-137.
Shafri MAM, Yusof FA, Zain AZM. 2015. In vitro cytotoxic activity of Ferula assafoetida on osteosarcoma cell line (HOS CRL). J Teknol, 77:7-11.
Shakeri A, Iranshahy M, Iranshahi M. 2014. Biological properties and molecular targets of umbelliprenin-a mini-review. J Asian Nat Prod Res, 16:884-889.
Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F, Behravan J. 2009. Evaluation of antigenotoxicity effects of umbelliprenin on human peripheral lymphocytes exposed to oxidative stress. Cell Biol Toxicol, 25:291-296.
Suzuki K, Okasaka M, Kashiwada Y, Takaishi Y, Honda G, Ito M, Takeda Y, Kodzhimatov OK, Ashurmetov O, Sekiya M, et al. 2007. Sesquiterpene lactones from the roots of Ferula varia and their cytotoxic activity. J Nat Prod, 70:1915-1918.
Tayeboon GS, Tavakoli F, Hassani S, Khanavi M, Sabzevari O, Ostad SN. 2013. Effects of Cymbopogon citratus and Ferula assa-foetida extracts on glutamate-induced neurotoxicity. In Vitro Cell Dev Biol Anim, 49:706-715.
Vahabi L, Shahanipour K, Monajemi R, Mortazavifar F. 2014. Study of Cytotoxic Effect of Methanolic Extract of Ferula assa-foetida Resin of Mashhad and Yazd on MDA-MB-231 Cell Line. Bulletin Environ Pharmacol Life Sci, 3:231-236.
Valiahdi SM, Iranshahi M, Sahebkar A. 2013. Cytotoxic activities of phytochemicals from Ferula species. DARU J Pharm Sci,. 21(39).
Yaqoob U, Nawchoo IA, Ahmad M. 2016. Phytochemical screening of the root tuber extracts of Ferula jaeschkeana vatke. J Essent Oil Bear Pl, 19:208-211.
Yu SM, Hu DH, Zhang JJ. 2015. Umbelliferone exhibits anticancer activity via the induction of apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells. Mol Med Rep, 12:3869-3873.
Zhang H, Lu J, Zhou L, Jiang L, Zhou M. 2015. Antioxidant and antitumor effects of Ferula sinkiangensis KM Shen. Int J Clin Exp Med, 8:20845-20852.
Zhang L, Tong X, Zhang J, Huang J, Wang J. 2015. DAW22, a natural sesquiterpene coumarin isolated from Ferula ferulaeoides (Steud.) Korov. that induces C6 glioma cell apoptosis and endoplasmic reticulum (ER) stress. Fitoterapia, 103:46-54.
Ziai SA, Gholami O, Iranshahi M, Zamani AH, Jeddi-Tehrani M. 2012. Umbelliprenin induces apoptosis in CLL cell lines. Iran J Pharm Res, 11:653-659.
Znati M, Ben Jannet H, Cazaux S, Souchard JP, Harzallah Skhiri F, Bouajila J. 2014a. Antioxidant, 5-lipoxygenase inhibitory and cytotoxic activities of compounds isolated from the Ferula lutea flowers. Molecules, 19:16959-16975.
Znati M, Jannet HB, Cazaux S, Bouajila J. 2014b. Chemical composition, biological and cytotoxic activities of plant extracts and compounds isolated from Ferula lutea. Molecules, 19:2733-2747.