Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells
Tóm tắt
Introduction Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds. This work was designed to assess the cytotoxicity and the mechanism of action of flavonoids abyssinone IV (1), atalantoflavone (3) and neocyclomorusin (6) and isoflavonoids sigmoidin I (2), sophorapterocarpan A (4), bidwillon A (5) and 6α-hydroxyphaseollidin (7) isolated from Erythrina sigmoidea against nine drug sensitive and multidrug resistant (MDR) cancer cell lines. Methods The resazurin reduction assay was used to evaluate the cytotoxicity of the studied compounds whilst caspase-Glo assay was used to detect the activation of caspases enzymes by 1, 2, 4 and 7. Cell cycle, mitochondrial membrane potential and levels of reactive oxygen species were all analyzed via flow cytometry. Results The pterocarpan isoflavonoid 7 displayed the best antiproliferative activity with the IC50 values below 10 μM obtained on the nine tested cancer cell lines. The IC50 values below 50 μM were also recorded with compounds 1, 2 and 4 against the nine cancer cell lines whilst 3, 5 and 6 showed selective activities. The IC50 values varied from 14.43 μM (against MDA-MB-231-pcDNA cells) to 20.65 μM [towards HCT116 (p53
+/+) cells] for compound 1, from 4.24 μM (towards CCRF-CEM cells) to 30.98 μM (towards MDA-MB-231-BCRP cells) for 2, from 3.73 μM (towards CCRF-CEM cells) to 14.81 μM (against U87MG.ΔEGFR cells) for 4, from 3.36 μM (towards CCRF-CEM cells) to 6.44 μM (against HepG2 cells) for 7, and from 0.20 μM (against CCRF-CEM cells) and 195.12 μM (against CEM/ADR5000 cells) for the positive control drug, doxorubicin. Compared to their corresponding sensitive cell lines, collateral sensitivity was observed with HCT116 (p53
−/−) to 1, 2, 4, 5, and 7 and with U87MG.ΔEGFR to 1 to 6. Compound 7 induced apoptosis in CCRF-CEM cells mediated by the activation of caspases 3/7, 8 and 9 and breakdown of MMP and increase in ROS production, whereas the apoptotic process induced by 1, 2 and 4 was mediated by the loss of MMP as well as increase in ROS production. Conclusions Compounds from Erythrina sigmoidea and mostly 6α-hydroxyphaseollidin are potential antiproliferative natural products that deserve more investigations to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.
Tài liệu tham khảo
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234
Efferth T (2001) The human ATP-binding cassette transporter genes: from the bench to the bedside. Curr Mol Med 1:45–65
Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580:998–1009
Gillet JP, Efferth T, Remacle J (2007) Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 1775:237–262
Cottiglia F, Casu L, Bonsignore L, Casu M, Floris C, Leonti M, Gertsch J, Heilmann J (2005) New cytotoxic prenylated isoflavonoids from Bituminaria morisiana. Planta Med 71:254–260
Militao GC, Pinheiro SM, Dantas IN, Pessoa C, de Moraes MO, Costa-Lotufo LC, Lima MA, Silveira ER (2007) Bioassay-guided fractionation of pterocarpans from roots of Harpalyce brasiliana Benth. Bioorg Med Chem 15(21):6687–6691
Nkengfack A, Kouam J, Vouffo T, Meyer M, Tempesta M, Fomum Z (1994) An isoflavanone and a coumestan from Erythrina sigmoidea. Phytochemistry 35:521–526
Kuete V, Ngameni B, Wiench B, Krusche B, Horwedel C, Ngadjui BT, Efferth T (2011) Cytotoxicity and mode of action of four naturally occuring flavonoids from the genus Dorstenia: Gancaonin Q, 4-hydroxylonchocarpin, 6-prenylapigenin, and 6,8-diprenyleriodictyol. Planta Med 77:1984–1989
Dzoyem JP, Nkuete AH, Kuete V, Tala MF, Wabo HK, Guru SK, Rajput VS, Sharma A, Tane P, Khan IA, Saxena AK, Laatsch H, Tan NH (2012) Cytotoxicity and antimicrobial activity of the methanol extract and compounds from Polygonum limbatum. Planta Med 78:787–792
Kuete V, Sandjo LP, Kwamou GM, Wiench B, Nkengfack AE, Efferth T (2014) Activity of three cytotoxic isoflavonoids from Erythrina excelsa and Erythrina senegalensis (neobavaisoflavone, sigmoidin H and isoneorautenol) toward multi-factorial drug resistant cancer cells. Phytomedicine 21:682–688
Yenesew A, Derese S, Irungu B, Midiwo JO, Waters NC, Liyala P, Akala H, Heydenreich M, Peter MG (2003) Flavonoids and isoflavonoids with antiplasmodial activities from the root bark of Erythrina abyssinica. Planta Med 69:658–661
Ndemangou B, Sielinou VT, Vardamides JC, Ali MS, Lateef M, Iqbal L, Afza N, Nkengfack AE (2013) Urease inhibitory isoflavonoids from different parts of Calopogonium mucunoides (Fabaceae). J Enzym Inhib 28:1156–1161
Iinuma M, Tanaka T, Mizuno M, Yamamoto H, Kobayashi Y, Yonemori S (1992) Phenolic constituents in Erythrina x bidwilli and their activity against oral microbial organisms. Chem Pharm Bull 40:2749–2752
Lee HJ, da Lyu H, Koo U, Nam KW, Hong SS, Kim KO, Kim KH, Lee D, Mar W (2012) Protection of prenylated flavonoids from Mori Cortex Radicis (Moraceae) against nitric oxide-induced cell death in neuroblastoma SH-SY5Y cells. Arch Pharm Res 35:163–170
Kimmig A, Gekeler V, Neumann M, Frese G, Handgretinger R, Kardos G, Diddens H, Niethammer D (1990) Susceptibility of multidrug-resistant human leukemia cell lines to human interleukin 2-activated killer cells. Cancer Res 50:6793–6799
Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 64:382–394
Gillet J, Efferth T, Steinbach D, Hamels J, de Longueville F, Bertholet V, Remacle J (2004) Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes. Cancer Res 64:8987–8993
Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 95:15665–15670
Kuete V, Tchakam PD, Wiench B, Ngameni B, Wabo HK, Tala MF, Moungang ML, Ngadjui BT, Murayama T, Efferth T (2013) Cytotoxicity and modes of action of four naturally occuring benzophenones: 2,2',5,6'-tetrahydroxybenzophenone, guttiferone E, isogarcinol and isoxanthochymol. Phytomedicine 20:528–536
Kuete V, Sandjo L, Nantchouang Ouete J, Fouotsa H, Wiench B, Efferth T (2013) Cytotoxicity and modes of action of three naturally occuring xanthones (8-hydroxycudraxanthone G, morusignin I and cudraxanthone I) against sensitive and multidrug-resistant cancer cell lines. Phytomedicine 21:315–322
Kuete V, Sandjo L, Wiench B, Efferth T (2013) Cytotoxicity and modes of action of four Cameroonian dietary spices ethno-medically used to treat Cancers: Echinops giganteus, Xylopia aethiopica, Imperata cylindrica and Piper capense. J Ethnopharmacol 149:245–253
O'Brien J, Wilson I, Orton T, Pognan F (2000) Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur J Biochem 267:5421–5426
Kuete V, Fankam AG, Wiench B, Efferth T (2003) Cytotoxicity and Modes of Action of the Methanol Extracts of Six Cameroonian Medicinal Plants against Multidrug-Resistant Tumor Cells. Evid Based Complement Alternat Med 2013:285903
Kuete V, Tankeo SB, Saeed ME, Wiench B, Tane P, Efferth T (2014) Cytotoxicity and modes of action of five Cameroonian medicinal plants against multi-factorial drug resistance of tumor cells. J Ethnopharmacol 153:207–219
Bass DA, Parce JW, Dechatelet LR, Szejda P, Seeds MC, Thomas M (1983) Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol 130:1910–1917
Cossarizza A, Ferraresi R, Troiano L, Roat E, Gibellini L, Bertoncelli L, Nasi M, Pinti M (2009) Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry. Nat Protoc 4:1790–1797
Bacher M, Brader G, Greger H, Hofer O (2010) Complete 1H and 13C NMR data assignment of new constituents from Severinia buxifolia. Magn Reson Chem 48:83–88
Jeong SH, Ryu YB, Curtis-Long MJ, Ryu HW, Baek YS, Kang JE, Lee WS, Park KH (2009) Tyrosinase inhibitory polyphenols from roots of Morus lhou. J Agric Food Chem 257:1195–1203
Nkengfack AE, Vouffo TW, Fomum ZT, Meyer M, Bergendorff O, Sterner O (1994) Prenylated isoflavanone from the roots of Erythrina sigmoidea. Phytochemistry 36:1047–1051
Ozaki Y, Mochida K, Kim S-W (1989) Total synthesis of sophorapterocarpan A, Maackiain and anhydropisatin : Application of a 1,3-Micheal-Claisen Annulation to aromatic synthesis. J Chem Soc Perkin Trans I:1219–1224
Nkengfack AE, Vardamides JC, Fomum ZT, Meyer M (1995) Prenylated isoflavanone from Erythrina eriotricha. Phytochemistry 40:1803–1808
Ingham J, Markham K (1980) Identification of the Erythrina phytoalexin cristacarpin and a note on the chirality of other 6a-hydroxypterocarpans. Phytochemistry 19:1203–1207
Shen B, Li D, Dong P, Gao S (2011) Expression of ABC transporters is an unfavorable prognostic factor in laryngeal squamous cell carcinoma. Ann Otol Rhinol Laryngol 120:820–827
Biedler JL, Spengler BA (1994) Reverse transformation of multidrug-resistant cells. Cancer Metastasis Rev 13:191–207
Efferth T, Sauerbrey A, Halatsch ME, Ross DD, Gebhart E (2003) Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. Naunyn Schmiedeberg's Arch Pharmacol 367:56–57
Eichhorn T, Efferth T (2012) P-glycoprotein and its inhibition in tumors by phytochemicals derived from Chinese herbs. J Ethnopharmacol 141:557–570
Baptiste N, Prives C (2004) p53 in the cytoplasm: a question of overkill? Cell 116:487–489
el-Deiry WS (1997) Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr Opin Oncol 9(1):79–87
Boik J (2001) Natural compounds in cancer therapy. Oregon Medical Press, Minnesota USA
Brahemi G, Kona FR, Fiasella A, Buac D, Soukupova J, Brancale A, Burger AM, Westwell AD (2010) Exploring the structural requirements for inhibition of the ubiquitin E3 ligase breast cancer associated protein 2 (BCA2) as a treatment for breast cancer. J Med Chem 53:2757–2765
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87:171
Ito C, Murata T, Itoigawa M, Nakao K, Kumagai M, Kaneda N, Furukawa H (2006) Induction of apoptosis by isoflavonoids from the leaves of Millettia taiwaniana in human leukemia HL-60 cells. Planta Med 72:424–429