Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Synergistic Growth Inhibitory Effects of Eryngium kotschyi Extracts with Conventional Cytotoxic Agents: Cisplatin and Doxorubicin against Human Endometrium Cancer Cells

Author(s): Ayşe Kübra Karaboğa Arslan*, Leyla Paşayeva, Merve Ayşe Esen and Osman Tugay

Volume 23, Issue 5, 2022

Published on: 26 August, 2021

Page: [740 - 748] Pages: 9

DOI: 10.2174/1389201022666210826160307

Price: $65


Background: Endometrial cancer is one of the most common types of cancer. For this reason, various studies have been carried out on its treatment and the effects of natural products on this disease.

Objectives: This study aimed to examine the growth inhibitory effects of Eryngium kotschyi Boiss. ethyl acetate [EKE] and butanol [EKB] obtained from the main methanol [EKM] extract from the aerial parts on human endometrium carcinoma [RL95-2] cells and their synergistic effect with cisplatin or doxorubicin.

Methods: RL95-2 cells were treated with E. kotschyi extracts either alone or in combination with cisplatin or doxorubicin. The effects on cell growth were determined using the MTT assay and real-time cell analysis xCELLigence.

Results: The extracts demonstrated growth inhibitory activity, with a certain degree of selectivity against the RL95-2 cell line. Synergistic effects of EKE/cisplatin or doxorubicin at different concentration levels were demonstrated in RL95-2 cells. In some instances, the EKE/doxorubicin combinations resulted in antagonistic effects. The reduction level of cell viability was different and specific to each combination for the RL95-2 cell line.

Conclusion: The growth inhibitory activity of cisplatin or doxorubicin, as a single agent, may be modified by combinations of the extracts and be synergistically enhanced in some cases. A significant synergistic effect of EKE on the RL95-2 cell line with cisplatin and doxorubicin was observed. This cytotoxic effect can be investigated in terms of molecular mechanisms. This study is the first of its kind in the literature. The mechanisms involved in this interaction between chemotherapeutic drugs and plant extracts remain unclear and should be further evaluated.

Keywords: Cisplatin, doxorubicin, endometrium cancer, Eryngium kotschyi, RL95-2, xCELLigence.

Graphical Abstract
Randall, M.E.; Filiaci, V.L.; Muss, H.; Spirtos, N.M.; Mannel, R.S.; Fowler, J.; Thigpen, J.T.; Benda, J.A. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J. Clin. Oncol., 2006, 24(1), 36-44.
[] [PMID: 16330675]
Markowska, A.; Pawałowska, M.; Lubin, J.; Markowska, J. Signalling pathways in endometrial cancer. Contemp. Oncol. (Pozn.), 2014, 18(3), 143-148.
[] [PMID: 25520571]
Çelik, A.; Aydınlık, N.; Arslan, I. Phytochemical constituents and inhibitory activity towards methicillin-resistant Staphylococcus aureus strains of Eryngium species (Apiaceae). Chem. Biodivers., 2011, 8(3), 454-459. [Apiaceae].
[] [PMID: 21404428]
Makki, R.; Dirani, Z.; Rammal, H.; Sweidan, A. Al bazzal, A.; Chokr, A. Antibacterial activity of two Lebanese plants: Eryngium creticum and Centranthus longiflorus. J. Nanomed. Nanotechnol., 2015, 6, 1-5.
Dunkić, V.; Vuko, E.; Bezić, N.; Kremer, D.; Ruščić, M. Composition and antiviral activity of the essential oils of Eryngium alpinum and E. amethystinum. Chem. Biodivers., 2013, 10(10), 1894-1902.
[] [PMID: 24130032]
Cavaleiro, C.; Gonçalves, M.J.; Serra, D.; Santoro, G.; Tomi, F.; Bighelli, A.; Salgueiro, L.; Casanova, J. Composition of a volatile extract of Eryngium duriaei subsp. juresianum (M. Laínz) M. Laínz, signalised by the antifungal activity. J. Pharm. Biomed. Anal., 2011, 54(3), 619-622.
[] [PMID: 21036502]
Abou-Jawdah, Y.; Sobh, H.; Salameh, A. Antimycotic activities of selected plant flora, growing wild in Lebanon, against phytopathogenic fungi. J. Agric. Food Chem., 2002, 50(11), 3208-3213.
[] [PMID: 12009988]
Derda, M.; Thiem, B.; Budzianowski, J.; Wojt, W.J.; Wojtkowiak-Giera, A. The evaluation of the amebicidal activity of Eryngium planum extracts. Acta Pol. Pharm., 2013, 70(6), 1027-1034.
[PMID: 24383326]
Fokialakis, N.; Kalpoutzakis, E.; Tekwani, B.L.; Khan, S.I.; Kobaisy, M.; Skaltsounis, A.L.; Duke, S.O. Evaluation of the antimalarial and antileishmanial activity of plants from the Greek island of Crete. J. Nat. Med., 2007, 61, 38-45.
Alkofahi, A.; Sallal, A.; Disi, A.M. Effect of Eryngium creticum on the haemolytic activities of snake and scorpion venoms. Phytother. Res., 1997, 11, 540-542.
Rammal, H.; Dammous, M.; Farhan, H.; Hijazi, A.; Bassal, A.; Fayyad-Kazan, H.; Badran, B.; Makhour, Y. Chemical composition of Lebanese Eryngium creticum L. Int. J. Sci., 2014, 3, 40-53.
Thomas, P.S.; Essien, E.E.; Ntuk, S.J.; Choudhary, M.I. Eryngium foetidum L. essential oils: chemical composition and antioxidant capacity. Medicines (Basel), 2017, 4(2), 24.
[] [PMID: 28930239]
Yurdakök, B.; Baydan, E. Cytotoxic effects of Eryngium kotschyi and Eryngium maritimum on Hep2, HepG2, Vero and U138 MG cell lines. Pharm. Biol., 2013, 51(12), 1579-1585.
[] [PMID: 24028780]
Khader, M.; Bresgen, N.; Eckl, P.M. Antimutagenic effects of ethanolic extracts from selected Palestinian medicinal plants. J. Ethnopharmacol., 2010, 127(2), 319-324.
[] [PMID: 19913082]
Kasabri, V.; Abu-Dahab, R.; Afifi, F.U.; Naffa, R.; Majdalawi, L. Modulation of pancreatic MIN6 insulin secretion and proliferation and extrapancreatic glucose absorption with Achillea santolina, Eryngium creticum and Pistacia atlantica extracts: In vitro evaluation. J. Exp. Integr. Med., 2012, 2, 245-254.
Küpeli, E.; Kartal, M.; Aslan, S.; Yeşilada, E. Comparative evaluation of the anti-inflammatory and antinociceptive activity of Turkish Eryngium species. J. Ethnopharmacol., 2006, 107(1), 32-37.
[] [PMID: 16529889]
Yesilada, E.; Tanaka, S.; Tabata, M.; Sezik, E. The antiinflammatory activity of the fractions from Eryngium billardieri in mice. Phytother. Res., 1989, 3, 38-40.
Gürhan, G.; Ezer, N. Halk arasında hemoroit tedavisinde kullanılan bitkiler. Hacettepe. Univ. Eczacı. Fak. Derg., 2004, 24, 37-55.
Tuzlacı, E. Türkiye Bitkileri Geleneksel İlaç Rehberi, 1st ed; İstanbul Tıp Kitabevleri: İstanbul, 2016, pp. 1212-1266.
Paşayeva, L.; Köngül, E.; Karatoparak, G.Ş.; Tugay, O. Eryngium billarderi Delar. Ekstrelerinin Toplam Fenolik ve Flavonoit Madde Kompozisyonlarinin ve Antioksidan Etkilerinin Belirlenmesi. Saglik. Bilim. Derg., 2016, 26, 18-23.
Kartal, M.; Mitaine-Offer, A.C.; Abu-Asaker, M.; Miyamoto, T.; Calis, I.; Wagner, H.; Lacaille-Dubois, M.A. Two new triterpene saponins from Eryngium campestre. Chem. Pharm. Bull. (Tokyo), 2005, 53(10), 1318-1320.
[] [PMID: 16204991]
Kartal, M.; Mitaine-Offer, A.C.; Paululat, T.; Abu-Asaker, M.; Wagner, H.; Mirjolet, J.F.; Guilbaud, N.; Lacaille-Dubois, M.A. Triterpene saponins from Eryngium campestre. J. Nat. Prod., 2006, 69(7), 1105-1108.
[] [PMID: 16872157]
Hansen, M.B.; Nielsen, S.E.; Berg, K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods, 1989, 119(2), 203-210.
[] [PMID: 2470825]
Karaboğa Arslan, A.K.; Yerer, M.B. α-Chaconine and α-solanine inhibit RL95-2 endometrium cancer cell proliferation by reducing expression of Akt [Ser473] and ERα. Nutrients, 2018, 10(6), 672. [Ser167].
[] [PMID: 29799481]
Burke, W.M.; Orr, J.; Leitao, M.; Salom, E.; Gehrig, P.; Olawaiye, A.B.; Brewer, M.; Boruta, D.; Herzog, T.J.; Shahin, F.A. Endometrial cancer: a review and current management strategies: part II. Gynecol. Oncol., 2014, 134(2), 393-402.
[] [PMID: 24929052]
Colombo, N.; Preti, E.; Landoni, F.; Carinelli, S.; Colombo, A.; Marini, C.; Sessa, C. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2013, 24(Suppl. 6), vi33-vi38.
[] [PMID: 24078661]
Erdem, S.A.; Arıhan, O.; Offer, A.M.; Iskit, A.; Miyamoto, T.; Kartal, M.; Lacaille Dubois, M. Antinociceptive activity of Eryngium kotschyi Boiss. root extracts. Planta Med., 2011, 77, PF66.
Ntalli, N.G.; Cottiglia, F.; Bueno, C.A.; Alché, L.E.; Leonti, M.; Vargiu, S.; Bifulco, E.; Menkissoglu-Spiroudi, U.; Caboni, P. Cytotoxic tirucallane triterpenoids from Melia azedarach fruits. Molecules, 2010, 15(9), 5866-5877.
[] [PMID: 20802401]
Podolak, I.; Galanty, A.; Sobolewska, D. Saponins as cytotoxic agents: A review. Phytochem. Rev., 2010, 9(3), 425-474.
[] [PMID: 20835386]
Matsubara, Y.; Matsumoto, T.; Koseki, J.; Kaneko, A.; Aiba, S.; Yamasaki, K. Inhibition of human kallikrein 5 protease by triterpenoids from natural sources. Molecules, 2017, 22(11), 1829.
[] [PMID: 29077044]
Ljubuncic, P.; Azaizeh, H.; Portnaya, I.; Cogan, U.; Said, O.; Saleh, K.A.; Bomzon, A. Antioxidant activity and cytotoxicity of eight plants used in traditional Arab medicine in Israel. J. Ethnopharmacol., 2005, 99(1), 43-47.
[] [PMID: 15848018]
Knauth, P.; Acevedo-Hernández, G.J.; Cano, M.E.; Gutiérrez-Lomelí, M.; López, Z. In vitro bioactivity of methanolic extracts from Amphipterygium adstringens [Schltdl.] Schiede ex Standl., Chenopodium ambrosioides L., Cirsium mexicanum DC., Eryngium carlinae F. Delaroche, and Pithecellobium dulce [Roxb] Benth. Used in traditional medicine in Mexico. Evid. Based Complement. Alternat. Med., 2018, 20183610364
[] [PMID: 29681972]
Rojas-Silva, P.; Graziose, R.; Vesely, B.; Poulev, A.; Mbeunkui, F.; Grace, M.H.; Kyle, D.E.; Lila, M.A.; Raskin, I. Leishmanicidal activity of a daucane sesquiterpene isolated from Eryngium foetidum. Pharm. Biol., 2014, 52(3), 398-401.
[] [PMID: 24147866]
Vukic, M.D.; Vukovic, N.L.; Djelic, G.T.; Obradovic, A.; Kacaniova, M.M.; Markovic, S.; Popović, S.; Baskić, D. Phytochemical analysis, antioxidant, antibacterial and cytotoxic activity of different plant organs of Eryngium serbicum L. Ind. Crops Prod., 2018, 115, 88-97.
Rzepecka-Stojko, A.; Kabała-Dzik, A.; Moździerz, A.; Kubina, R.; Wojtyczka, R.D.; Stojko, R.; Dziedzic, A.; Jastrzębska-Stojko, Ż.; Jurzak, M.; Buszman, E.; Stojko, J. Caffeic Acid phenethyl ester and ethanol extract of propolis induce the complementary cytotoxic effect on triple-negative breast cancer cell lines. Molecules, 2015, 20(5), 9242-9262.
[] [PMID: 26007182]
Ekbatan, S.S.; Li, X.; Ghorbani, M.; Azadi, B.; Kubow, S. Chlorogenic acid and its microbial metabolites exert antiproliferative effects, s-phase cell-cycle arrest and apoptosis in human colon cancer caco-2 cells. Int. J. Mol. Sci., 2018, 19, 723.
Jang, Y.G.; Hwang, K.A.; Choi, K.C. Rosmarinic acid, a component of rosemary tea, induced the cell cycle arrest and apoptosis through modulation of HDAC2 expression in prostate cancer cell lines. Nutrients, 2018, 10(11), 1784.
[] [PMID: 30453545]
Tungmunnithum, D.; Thongboonyou, A.; Pholboon, A.; Yangsabai, A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: an overview. Medicines (Basel), 2018, 5(3), 93.
[] [PMID: 30149600]
Zhang, J.; Shi, G.W. Inhibitory effect of solanine on prostate cancer cell line PC-3 in vitro. Zhonghua Nan Ke Xue, 2011, 17(3), 284-287.
[PMID: 21485553]
Rejhová, A.; Opattová, A.; Čumová, A.; Slíva, D.; Vodička, P. Natural compounds and combination therapy in colorectal cancer treatment. Eur. J. Med. Chem., 2018, 144, 582-594.
[] [PMID: 29289883]
Chamberlin, S.R.; Blucher, A.; Wu, G.; Shinto, L.; Choonoo, G.; Kulesz-Martin, M.; McWeeney, S. Natural product target network reveals potential for cancer combination therapies. Front. Pharmacol., 2019, 10, 557.
[] [PMID: 31214023]
Sauter, E.R. Cancer prevention and treatment using combination therapy with natural compounds. Expert Rev. Clin. Pharmacol., 2020, 13(3), 265-285.
[] [PMID: 32154753]
Sanders, K.; Moran, Z.; Shi, Z.; Paul, R.; Greenlee, H. Natural products for cancer prevention: Clinical update 2016. Semin. Oncol. Nurs., 2016, 32(3), 215-240.
[] [PMID: 27539278]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy