Synergistic Cytotoxic and Anti-invasive Effects of Mitoxantrone and Triterpene Saponins from Lysimachia ciliata on Human Prostate Cancer Cells

Abstract

Triterpene saponins are secondary metabolites typical for higher plants. They possess a wide range of pharmaceutical and biological activities. These include anti-inflammatory, vasoprotective, expectorant, and antitumor properties. In particular, the ability of saponins to enhance the cytotoxicity of chemotherapeutic drugs has opened new perspectives for their application in combined cancer chemotherapy. In this study, the biological activity of the saponin fraction isolated from Lysimachia ciliata (denoted as CIL-1/2) was evaluated to assess its chemosensitizing activity in prostate cancer cell lines (DU-145, PC-3). No cytotoxic or cytostatic effect of the CIL-1/2 fraction administered at the concentration of 0.5 µg/mL was observed. In contrast, cocktails of CIL-1/2 and mitoxantrone (a drug commonly used in prostate cancer therapy) exerted synergistic cytostatic and proapoptotic effects. Furthermore, the synergy of proapoptotic activities of the analyzed cocktails is accompanied by their synergistic effects on prostate cancer cell movement and invasiveness. The significantly weaker impact of this cocktail on normal prostate cells additionally adds to the significance of our data and confirms that the CIL-1/2 fraction might be considered a potent adjuvant for prostate cancer chemotherapy.

Key words

Lysimachia ciliata - Primulaceae - triterpene saponins - mitoxantrone - prostate cancer - proliferation - apoptosis - cell motility

• References

• 1 Jang KJ, Choi SH, Yu GJ, Hong SH, Chung YH, Kim CH, Yoon HM, Kim GY, Kim BW, Choi YH. Anti-inflammatory potential of total saponins derived from the roots of Panax ginseng in lipopolysaccharide-activated RAW 264.7 macrophages. Exp Ther Med 2016; 11: 1109-1115
• 2 Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of Korean Red Ginseng (Panax ginseng Meyer): History, preparation method, and chemical composition. J Ginseng Res 2015; 39: 384-391
• 3 Gandaglia G, Suardi N, Cucchiara V, Bianchi M, Shariat SF, Roupret M, Salonia A, Montorsi F, Briganti A. Penile rehabilitation after radical prostatectomy: does it work?. Transl Androl Urol 2015; 4: 110-123
• 4 Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, Blackburn J, Arora T, Kilgore ML. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 2011; 14: 177-183
• 5 Schweizer MT, Antonarakis ES. Chemotherapy and its evolving role in the management of advanced prostate cancer. Asian J Androl 2014; 16: 334-340
• 6 Rivera VM, Jeffery DR, Weinstock-Guttman B, Bock D, Dangond F. Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study. BMC Neurol 2013; 13: 80
• 7 Fleming MT, Sonpavde G, Kolodziej M, Awasthi S, Hutson TE, Martincic D, Rastogi A, Rousey SR, Weinstein RE, Galsky MD, Berry WR, Wang Y, Boehm KA, Asmar L, Rauch MA, Beer TM. Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 2012; 10: 6-14
• 8 Eid SY, El-Readi MZ, Wink M. Digitonin synergistically enhances the cytotoxicity of plant secondary metabolites in cancer cells. Phytomedicine 2012; 19: 1307-1314
• 9 Gilabert-Oriol R, Weng A, Trautner A, Weise C, Schmid D, Bhargava C, Niesler N, Wookey PJ, Fuchs H, Thakur M. Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861. Biochem Pharmacol 2015; 97: 247-255
• 10 Koczurkiewicz P, Czyż J, Podolak I, Wójcik K, Galanty A, Janeczko Z, Michalik M. Multidirectional effects of triterpene saponins on cancer cells – mini-review of in vitro studies. Acta Biochim Pol 2015; 62: 383-393
• 11 Podolak I, Galanty A, Sobolewska D. Saponins as cytotoxic agents: a review. Phytochem Rev 2010; 9: 425-474
• 12 Fuchs H, Bachran D, Panjideh H, Schellmann N, Weng A, Melzig MF, Sutherland M, Bachran C. Saponins as tool for improved targeted tumor therapies. Curr Drug Targets 2009; 10: 140-151
• 13 Koczurkiewicz P, Podolak I, Wójcik KA, Galanty A, Madeja Z, Michalik M, Czyż J. Lclet 4 enhances pro-apoptotic and anti-invasive effects of mitoxantrone on human prostate cancer cells – in vitro study. Acta Biochim Pol 2013; 60: 331-338
• 14 Koczurkiewicz P, Podolak I, Skrzeczyńska-Moncznik J, Sarna M, Wójcik KA, Ryszawy D, Galanty A, Lasota S, Madeja Z, Czyż J, Michalik M. Triterpene saponosides from Lysimachia ciliata differentially attenuate invasive potential of prostate cancer cells. Chem Biol Interact 2013; 206: 6-17
• 15 Foubert K, Theunis M, Apers S, Vlietinck AJ, Pieters L. Chemistry, distribution and biological activities of 13,28-epoxy-oleanane saponins from the plant families Myrsinaceae and Primulaceae. Curr Org Chem 2008; 12: 629-642
• 16 Glombitza KW, Kurth H. Saponine aus Anagallis arvensis L. (Primulaceae). Arch Pharm 1987; 320: 1083-1087
• 17 Mahato SB, Sahu NP, Roy SK, Sen S. Structure elucidation of four new triterpenoid oligoglycosides from Anagallis arvensis . Tetrahedron 1991; 47: 5215-5230
• 18 Shoji N, Umeyama A, Yoshikawa K, Arihara S. Triterpenoid glycosides from Anagallis arvensis . Phytochemistry 1994; 37: 1397-1402
• 19 Abdel-Gawad MM, El-Amin SM, Ohigashi H, Watanabe Y, Takeda N, Sugiyama H, Kawanaka M. Molluscicidal saponins from Anagallis arvensis against schistosome intermediate hosts. Jpn J Infect Dis 2000; 53: 17-19
• 20 DallʼAcqua S, Castagliuolo I, Brun P, Ditadi F, Palù G, Innocenti G. Triterpene glycosides with in vitro anti-inflammatory activity from Cyclamen repandum tubers. Carbohydr Res 2010; 345: 709-714
• 21 Lee JH, Oh EK, Cho HD, Kim JY, Lee MK, Seo KI. Crude saponins from Platycodon grandiflorum induce apoptotic cell death in RC-58T/h/SA#4 prostate cancer cells through the activation of caspase cascades and apoptosis-inducing factor. Oncol Rep 2013; 29: 1421-1428
• 22 Cheng TC, Lu JF, Wang JS, Lin LJ, Kuo HI, Chen BH. Antiproliferation effect and apoptosis mechanism of prostate cancer cell PC-3 by flavonoids and saponins prepared from Gynostemma pentaphyllum . J Agric Food Chem 2011; 59: 11319-11329
• 23 Ulrich-Merzenich G. Combination screening of synthetic drugs and plant derived natural products – potential and challenges for drug development. Synergy 2014; 1: 59-69
• 24 Herrmann F, Wink M. Synergistic interactions of saponins and monoterpenes in HeLa cells, Cos7 cells and in erythrocytes. Phytomedicine 2011; 18: 1191-1196
• 25 Zhang C, Tong X, Qi B, Yu X, Dong S, Zhang S, Li X, Yu M. Components of Panax notoginseng saponins enhance the cytotoxicity of cisplatin via their effects on gap junctions. Mol Med Rep 2013; 8: 897-902
• 26 Liu W, Di Giorgio C, Lamidi M, Elias R, Ollivier E, De Méo MP. Genotoxic and clastogenic activity of saponins extracted from Nauclea bark as assessed by the micronucleus and the comet assays in Chinese Hamster Ovary cells. J Ethnopharmacol 2011; 137: 176-183
• 27 Arslan I, Ili P. Genotoxicological assessment of nebuloside-A a triterpenoid saponin compound on whole blood DNA. Int J Food Prop 2015; 18: 2374-2379
• 28 Li Q, Deng L, Li W, Koike K. Cyclamin, a natural 13,28-epoxy triterpenoid saponin, synergistically enhances the cytotoxicity of chemotherapeutic drugs in human liver cancer cells but not non-neoplastic liver cells. Planta Med 2014; 80: 409-414
• 29 Fishbein AB, Wang CZ, Li XL, Mehendale SR, Sun S, Aung HH, Yuan CS. Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng. Arch Pharm Res 2009; 32: 505-513
• 30 Liang Y, Xu X, Yu H, Li L, Hong T, Ji Q, Feng Y, Jin S, Song Y, Guo J, Zheng Z, Ye Q, Yang S. Raddeanoside R13 inhibits breast cancer cell proliferation, invasion, and metastasis. Tumour Biol 2016;
• 31 Zhao PJ, Song SC, Du LW, Zhou GH, Ma SL, Li JH, Feng JG, Zhu XH, Jiang H. Paris saponins enhance radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line by inducing apoptosis and G2/M cell cycle phase arrest. Mol Med Rep 2016; 13: 2878-2884
• 32 Lee WH, Choi JS, Kim HY, Park JH, Park BD, Cho SJ, Lee SK, Surh YJ. Potentiation of etoposide-induced apoptosis in HeLa cells by co-treatment with KG-135, a quality-controlled standardized ginsenoside formulation. Cancer Lett 2010; 294: 74-81
• 33 Harikumar KB, Sung B, Pandey MK, Guha S, Krishnan S, Aggarwal BB. Escin, a pentacyclic triterpene, chemosensitizes human tumor cells through inhibition of nuclear factor-kappaB signaling pathway. Mol Pharmacol 2010; 77: 818-827
• 34 Gu Y, Wang G, Sun J, Xie H, Yia Y. Development of a sensitive LC-ESI-MS assay for 20(R)-ginsenoside Rh2 and its pharmacokinetic application in dogs: a case for the influence of micronization on traditional Chinese medicine. Int J Mass Spectrom 2006; 252: 11-19
• 35 Greco WR, Bravo G, Parsons JC. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev 1995; 47: 331-385
• 36 Podolak I, Koczurkiewicz P, Galanty A, Michalik M. Cytotoxic triterpene saponins from the underground parts of six Lysimachia L. species. Biochem Syst Ecol 2013; 47: 116-120
• 37 Pękala E, Liana P, Kubowicz P, Powroźnik B, Obniska J, Chlebek I, Węgrzyn A, Węgrzyn G. Evaluation of mutagenic and antimutagenic properties of new derivatives of pyrrolidine-2,5-dione with anti-epileptic activity, by use of the Vibrio harveyi mutagenicity test. Mutat Res 2013; 758: 18-22
• 38 Gillies RJ, Didier N, Denton M. Determination of cell number in monolayer cultures. Anal Biochem 1986; 159: 109-113
• 39 Galanty A, Michalik M, Sędek L, Podolak I. The influence of LTS-4, a saponoside from Lysimachia thyrsiflora L., on human skin fibroblasts and human melanoma cells. Cell Mol Biol Lett 2008; 13: 585-598
• 40 Madeja Z, Miękus K, Sroka J, Djamgoz MB, Korohoda W. Homotypic cell-cell contacts stimulate the motile activity of rat prostate cancer cells. BJU Int 2001; 7: 776-786