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Erschienen in: European Journal of Nutrition 4/2018

10.03.2017 | Original Contribution

Antiproliferative activity of vitexin-2-O-xyloside and avenanthramides on CaCo-2 and HepG2 cancer cells occurs through apoptosis induction and reduction of pro-survival mechanisms

verfasst von: Emanuele Salvatore Scarpa, Elena Antonini, Francesco Palma, Michele Mari, Paolino Ninfali

Erschienen in: European Journal of Nutrition | Ausgabe 4/2018

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Abstract

Purpose

CaCo-2 colon cancer cells and HepG2 liver cancer cells represent two malignant cell lines, which show a high resistance to apoptosis induced by the conventional anticancer drugs. Vitexin-2-O-xyloside (XVX) and avenanthramides (AVNs) are naturally occurring dietary agents from Beta vulgaris var. cicla L. and Avena sativa L., respectively. The aim of this work was to evaluate the antiproliferative effects and the reduction of the pro-survival mechanisms exerted by XVX and AVNs, used individually and in combination, in CaCo-2 and HepG2 cancer cells.

Methods

XVX and AVNs were isolated by liquid chromatography and characterized by HPLC–PDA–MS. The XVX and AVN antiproliferative effects were evaluated through sulforhodamine B method, while their pro-apoptotic effects through caspase activity assays. RTqPCR was used to investigate the modulation of the pro-survival factors baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), hypoxia inducible factor 1 A (HIF1A), and vascular endothelial growth factor A (VEGFA). Cellular antioxidant activity (CAA) was investigated by means of DCFH-DA assay, whereas chemical antioxidant capacity was evaluated by the ORAC method.

Results

XVX and AVNs, both individually and in combination, inhibited the proliferation of CaCo-2 and HepG2 cancer cells, through activation of caspases 9, 8, and 3. XVX and AVNs downregulated the pro-survival genes BIRC5, HIF1A, and VEGFA. The CAA assay showed that AVNs exhibited strong antioxidant activity inside both CaCo-2 and HepG2 cells.

Conclusions

The antiproliferative activity of the XVX + AVNs mixture represents an innovative treatment, which is effective against two types of cancer cells characterized by high resistance to the conventional anticancer drugs.
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Literatur
1.
Zurück zum Zitat Ninfali P, Bacchiocca M, Antonelli A, Biagiotti E, Di Gioacchino AM, Piccoli G, Stocchi V, Brandi G (2007) Characterization and biological activity of the main flavonoids from Swiss Chard (Beta vulgaris subspecies cycla). Phytomedicine 14:216–221CrossRefPubMed Ninfali P, Bacchiocca M, Antonelli A, Biagiotti E, Di Gioacchino AM, Piccoli G, Stocchi V, Brandi G (2007) Characterization and biological activity of the main flavonoids from Swiss Chard (Beta vulgaris subspecies cycla). Phytomedicine 14:216–221CrossRefPubMed
2.
Zurück zum Zitat Ninfali P, Angelino D (2013) Nutritional and functional potential of Beta vulgaris cicla and rubra. Fitoterapia 89:188–199CrossRefPubMed Ninfali P, Angelino D (2013) Nutritional and functional potential of Beta vulgaris cicla and rubra. Fitoterapia 89:188–199CrossRefPubMed
3.
Zurück zum Zitat Gennari L, Felletti M, Blasa M, Angelino D, Celeghini C, Corallini A, Ninfali P (2011) Total extract of Beta vulgaris var. cicla seeds versus its purified phenolic components: antioxidant activities and antiproliferative effects against colon cancer cells. Phytochem Anal 22:272–279CrossRefPubMed Gennari L, Felletti M, Blasa M, Angelino D, Celeghini C, Corallini A, Ninfali P (2011) Total extract of Beta vulgaris var. cicla seeds versus its purified phenolic components: antioxidant activities and antiproliferative effects against colon cancer cells. Phytochem Anal 22:272–279CrossRefPubMed
4.
Zurück zum Zitat Papi A, Farabegoli F, Iori R, Orlandi M, De Nicola GR, Bagatta M, Angelino D, Gennari L, Ninfali P (2013) Vitexin-2-0-xyloside, raphasatin and (–)-epigallocatechin-3-gallate synergistically affect cell growth and apoptosis of colon cancer cells. Food Chem 138:1521–1530CrossRefPubMed Papi A, Farabegoli F, Iori R, Orlandi M, De Nicola GR, Bagatta M, Angelino D, Gennari L, Ninfali P (2013) Vitexin-2-0-xyloside, raphasatin and (–)-epigallocatechin-3-gallate synergistically affect cell growth and apoptosis of colon cancer cells. Food Chem 138:1521–1530CrossRefPubMed
5.
Zurück zum Zitat Farabegoli F, Scarpa ES, Frati A, Serafini G, Papi A, Spisni E, Antonini E, Benedetti S, Ninfali P (2017) Betalains increase vitexin-2-O-xyloside cytotoxicity in CaCo-2 cancer cells. Food Chem 218:356–364CrossRefPubMed Farabegoli F, Scarpa ES, Frati A, Serafini G, Papi A, Spisni E, Antonini E, Benedetti S, Ninfali P (2017) Betalains increase vitexin-2-O-xyloside cytotoxicity in CaCo-2 cancer cells. Food Chem 218:356–364CrossRefPubMed
6.
7.
Zurück zum Zitat Collins FW (1989) Oat phenolics: avenanthramides, novel substituted N-cinnamoylanthranilate alkaloids from oat groats and hulls. J Agric Food Chem 37:60–66CrossRef Collins FW (1989) Oat phenolics: avenanthramides, novel substituted N-cinnamoylanthranilate alkaloids from oat groats and hulls. J Agric Food Chem 37:60–66CrossRef
8.
Zurück zum Zitat Antonini E, Lombardi F, Alfieri M, Diamantini G, Redaelli R, Ninfali P (2016) Nutritional characterization of naked and dehulled oat cultivar samples at harvest and after storage. J Cereal Sci 72:46–53CrossRef Antonini E, Lombardi F, Alfieri M, Diamantini G, Redaelli R, Ninfali P (2016) Nutritional characterization of naked and dehulled oat cultivar samples at harvest and after storage. J Cereal Sci 72:46–53CrossRef
9.
Zurück zum Zitat Skoglund M, Peterson DM, Andersson R, Nilsson J, Dimberg LH (2008) Avenanthramide content and related enzyme activities in oats as affected by steeping and germination. J Cereal Sci 48:294–303CrossRef Skoglund M, Peterson DM, Andersson R, Nilsson J, Dimberg LH (2008) Avenanthramide content and related enzyme activities in oats as affected by steeping and germination. J Cereal Sci 48:294–303CrossRef
10.
Zurück zum Zitat Xu JG, Tian CR, Hu QP, Luo JY, Wang XD, Tian XD (2009) Dynamic changes in phenolic compounds and antioxidant activity in oats (Avena nuda L.) during steeping and germination. J Agric Food Chem 57:10392–10398CrossRefPubMed Xu JG, Tian CR, Hu QP, Luo JY, Wang XD, Tian XD (2009) Dynamic changes in phenolic compounds and antioxidant activity in oats (Avena nuda L.) during steeping and germination. J Agric Food Chem 57:10392–10398CrossRefPubMed
11.
Zurück zum Zitat Chen CY, Milbury PE, Kwak HK, Collins FW, Samuel P, Blumberg JB (2004) Avenanthramides and phenolic acids from oats are bioavailable and act synergistically with vitamin C to enhance hamster and human LDL resistance to oxidation. J Nutr 134:1459–1466CrossRefPubMed Chen CY, Milbury PE, Kwak HK, Collins FW, Samuel P, Blumberg JB (2004) Avenanthramides and phenolic acids from oats are bioavailable and act synergistically with vitamin C to enhance hamster and human LDL resistance to oxidation. J Nutr 134:1459–1466CrossRefPubMed
12.
Zurück zum Zitat Chen CYO, Milbury PE, Collins FW, Blumberg JB (2007) Avenanthramides are bioavailable and have antioxidant activity in humans after acute consumption of an enriched mixture from oats. J Nutr 137:1375–1382CrossRefPubMed Chen CYO, Milbury PE, Collins FW, Blumberg JB (2007) Avenanthramides are bioavailable and have antioxidant activity in humans after acute consumption of an enriched mixture from oats. J Nutr 137:1375–1382CrossRefPubMed
13.
Zurück zum Zitat Koenig RT, Dickman JR, Wise ML, Ji LL (2011) Avenanthramides are bioavailable and accumulate in hepatic, cardiac, and skeletal muscle tissue following oral gavage in rats. J Agric Food Chem 59:6438–6443CrossRefPubMed Koenig RT, Dickman JR, Wise ML, Ji LL (2011) Avenanthramides are bioavailable and accumulate in hepatic, cardiac, and skeletal muscle tissue following oral gavage in rats. J Agric Food Chem 59:6438–6443CrossRefPubMed
14.
15.
Zurück zum Zitat Guo WM, Nie L, Wu DY, Wise ML, Collins FW, Meydani SN, Meydani M (2010) Avenanthramides inhibit proliferation of human colon cancer cell lines in vitro. Nutr Cancer 62:1007–1016CrossRefPubMed Guo WM, Nie L, Wu DY, Wise ML, Collins FW, Meydani SN, Meydani M (2010) Avenanthramides inhibit proliferation of human colon cancer cell lines in vitro. Nutr Cancer 62:1007–1016CrossRefPubMed
16.
17.
Zurück zum Zitat Samali A, Jager R (2014) Mechanisms of resistance to cell death pathways in cancer cells. In: McManus LM, Mitchell RN (eds) Pathobiology of human disease, 1st edn. Elsevier Inc., Atlanta, pp 393–402CrossRef Samali A, Jager R (2014) Mechanisms of resistance to cell death pathways in cancer cells. In: McManus LM, Mitchell RN (eds) Pathobiology of human disease, 1st edn. Elsevier Inc., Atlanta, pp 393–402CrossRef
19.
Zurück zum Zitat Johnson ME, Howerth EW (2004) Survivin: a bifunctional inhibitor of apoptosis protein. Vet Pathol 41:599–607CrossRefPubMed Johnson ME, Howerth EW (2004) Survivin: a bifunctional inhibitor of apoptosis protein. Vet Pathol 41:599–607CrossRefPubMed
20.
Zurück zum Zitat Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRef Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRef
21.
Zurück zum Zitat Gomez-Roman N, Sahasrabudhe NM, McGregor F, Chalmers AJ, Cassidy J, Plumb J (2016) Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer. Oncotarget 7:22650–22664CrossRefPubMedPubMedCentral Gomez-Roman N, Sahasrabudhe NM, McGregor F, Chalmers AJ, Cassidy J, Plumb J (2016) Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer. Oncotarget 7:22650–22664CrossRefPubMedPubMedCentral
22.
23.
Zurück zum Zitat Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor-1 is a basic-helix–loop–helix-pas heterodimer regulated by cellular O-2 tension. Proc Natl Acad Sci USA 92:5510–5514CrossRefPubMed Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor-1 is a basic-helix–loop–helix-pas heterodimer regulated by cellular O-2 tension. Proc Natl Acad Sci USA 92:5510–5514CrossRefPubMed
24.
Zurück zum Zitat Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, Chung DC, Giovannucci EL, Fuchs CS, Ogino S (2010) HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176:2292–2301CrossRefPubMedPubMedCentral Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, Chung DC, Giovannucci EL, Fuchs CS, Ogino S (2010) HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176:2292–2301CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Ferrara N (2005) VEGF as a therapeutic target in cancer. Int Soc Cell 69:11–16 Ferrara N (2005) VEGF as a therapeutic target in cancer. Int Soc Cell 69:11–16
26.
Zurück zum Zitat Ellis LM, Takahashi Y, Liu W, Shaheen RM (2000) Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 5:11–15CrossRefPubMed Ellis LM, Takahashi Y, Liu W, Shaheen RM (2000) Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 5:11–15CrossRefPubMed
27.
Zurück zum Zitat Doll JA, Hobbs JE, Soff JA (2007) Role of apoptosis in anti-angiogenic cancer therapies. In: Gewirtz DA, Holt SE, Grant S (eds) Apoptosis and senescence in cancer chemotherapy and radiotherapy, 2nd edn. Humana Press, Totowa, pp 537–555 Doll JA, Hobbs JE, Soff JA (2007) Role of apoptosis in anti-angiogenic cancer therapies. In: Gewirtz DA, Holt SE, Grant S (eds) Apoptosis and senescence in cancer chemotherapy and radiotherapy, 2nd edn. Humana Press, Totowa, pp 537–555
28.
Zurück zum Zitat Piccirillo S, Filomeni G, Brune B, Rotilio G, Ciriolo MR (2009) Redox mechanisms involved in the selective activation of Nrf2-mediated resistance versus p53-dependent apoptosis in adenocarcinoma cells. J Biol Chem 284:27721–27733CrossRefPubMedPubMedCentral Piccirillo S, Filomeni G, Brune B, Rotilio G, Ciriolo MR (2009) Redox mechanisms involved in the selective activation of Nrf2-mediated resistance versus p53-dependent apoptosis in adenocarcinoma cells. J Biol Chem 284:27721–27733CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Heo SH, Kwak J, Jang KL (2015) All-trans retinoic acid induces p53-dependent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation. Cancer Lett 362:139–148CrossRefPubMed Heo SH, Kwak J, Jang KL (2015) All-trans retinoic acid induces p53-dependent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation. Cancer Lett 362:139–148CrossRefPubMed
30.
Zurück zum Zitat Ye RP, Chen ZD (2017) Saikosaponin A, an active glycoside from Radix bupleuri, reverses P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells and HepG2/ADM cells. Xenobiotica 47:176–184CrossRefPubMed Ye RP, Chen ZD (2017) Saikosaponin A, an active glycoside from Radix bupleuri, reverses P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells and HepG2/ADM cells. Xenobiotica 47:176–184CrossRefPubMed
31.
Zurück zum Zitat Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592CrossRefPubMed Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592CrossRefPubMed
32.
Zurück zum Zitat Liu LP, Zubik L, Collins FW, Marko M, Meydani M (2004) The antiatherogenic potential of oat phenolic compounds. Atherosclerosis 175:39–49CrossRefPubMed Liu LP, Zubik L, Collins FW, Marko M, Meydani M (2004) The antiatherogenic potential of oat phenolic compounds. Atherosclerosis 175:39–49CrossRefPubMed
33.
Zurück zum Zitat Ninfali P, Gennari L, Biagiotti E, Cangi F, Mattoli L, Maidecchi A (2009) Improvement in botanical standardization of commercial freeze-dried herbal extracts by using the combination of antioxidant capacity and constituent marker concentrations. J AOAC Int 92:797–805PubMed Ninfali P, Gennari L, Biagiotti E, Cangi F, Mattoli L, Maidecchi A (2009) Improvement in botanical standardization of commercial freeze-dried herbal extracts by using the combination of antioxidant capacity and constituent marker concentrations. J AOAC Int 92:797–805PubMed
34.
Zurück zum Zitat Wang Y, Tang Q, Jiang S, Li M, Wang X (2013) Anti-colorectal cancer activity of macrostemonoside A mediated by reactive oxygen species. Biochem Biophys Res Commun 441:825–830CrossRef Wang Y, Tang Q, Jiang S, Li M, Wang X (2013) Anti-colorectal cancer activity of macrostemonoside A mediated by reactive oxygen species. Biochem Biophys Res Commun 441:825–830CrossRef
35.
Zurück zum Zitat Scarpa ES, Emanuelli M, Frati A, Pozzi V, Antonini E, Diamantini G, Di RG, Sartini D, Armeni T, Palma F, Ninfali P (2016) Betacyanins enhance vitexin-2-O-xyloside mediated inhibition of proliferation of T24 bladder cancer cells. Food Funct 7:4772–4780CrossRefPubMed Scarpa ES, Emanuelli M, Frati A, Pozzi V, Antonini E, Diamantini G, Di RG, Sartini D, Armeni T, Palma F, Ninfali P (2016) Betacyanins enhance vitexin-2-O-xyloside mediated inhibition of proliferation of T24 bladder cancer cells. Food Funct 7:4772–4780CrossRefPubMed
36.
Zurück zum Zitat Peterson DM, Hahn MJ, Emmons CL (2002) Oat avenanthramides exhibit antioxidant activities in vitro. Food Chem 79:473–478CrossRef Peterson DM, Hahn MJ, Emmons CL (2002) Oat avenanthramides exhibit antioxidant activities in vitro. Food Chem 79:473–478CrossRef
37.
38.
Zurück zum Zitat Huang H, Chen AY, Rojanasakul Y, Ye X, Rankin GO, Chen YC (2015) Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis. J Funct Foods 15:464–475CrossRefPubMedPubMedCentral Huang H, Chen AY, Rojanasakul Y, Ye X, Rankin GO, Chen YC (2015) Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis. J Funct Foods 15:464–475CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Angelino D, Berhow M, Ninfali P, Jeffery EH (2013) Caecal absorption of vitexin-2-O-xyloside and its aglycone apigenin, in the rat. Food Funct 4:1339–1345CrossRefPubMed Angelino D, Berhow M, Ninfali P, Jeffery EH (2013) Caecal absorption of vitexin-2-O-xyloside and its aglycone apigenin, in the rat. Food Funct 4:1339–1345CrossRefPubMed
40.
Zurück zum Zitat Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947CrossRefPubMed Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947CrossRefPubMed
41.
Zurück zum Zitat Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA 99:715–720CrossRefPubMed Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA 99:715–720CrossRefPubMed
42.
Zurück zum Zitat Zhang Y, Zhao W, Zhang HJ, Domann FE, Oberley LW (2002) Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth. Cancer Res 62:1205–1212PubMed Zhang Y, Zhao W, Zhang HJ, Domann FE, Oberley LW (2002) Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth. Cancer Res 62:1205–1212PubMed
43.
Zurück zum Zitat Ueda S, Nakamura H, Masutani H, Sasada T, Takabayashi A, Yamaoka Y, Yodoi J (2002) Baicalin induces apoptosis via mitochondrial pathway as prooxidant. Mol Immunol 38:781–791CrossRefPubMed Ueda S, Nakamura H, Masutani H, Sasada T, Takabayashi A, Yamaoka Y, Yodoi J (2002) Baicalin induces apoptosis via mitochondrial pathway as prooxidant. Mol Immunol 38:781–791CrossRefPubMed
44.
Zurück zum Zitat Ismail N, Alam M (2001) A novel cytotoxic flavonoid glycoside from Physalis angulata. Fitoterapia 72:676–679CrossRefPubMed Ismail N, Alam M (2001) A novel cytotoxic flavonoid glycoside from Physalis angulata. Fitoterapia 72:676–679CrossRefPubMed
45.
Zurück zum Zitat Cao G, Sofic E, Prior RL (1997) Antioxidant and prooxidant behavior of flavonoids: structure–activity relationships. Free Radic Biol Med 22:749–760CrossRefPubMed Cao G, Sofic E, Prior RL (1997) Antioxidant and prooxidant behavior of flavonoids: structure–activity relationships. Free Radic Biol Med 22:749–760CrossRefPubMed
46.
Zurück zum Zitat Choi HJ, Eun JS, Kim BG, Kim SY, Jeon H, Soh Y (2006) Vitexin, an HIF-1alpha inhibitor, has anti-metastatic potential in PC12 cells. Mol Cells 22:291–299PubMed Choi HJ, Eun JS, Kim BG, Kim SY, Jeon H, Soh Y (2006) Vitexin, an HIF-1alpha inhibitor, has anti-metastatic potential in PC12 cells. Mol Cells 22:291–299PubMed
47.
Zurück zum Zitat Ma J, Feng Y, Liu Y, Li X (2016) PUMA and survivin are involved in the apoptosis of HepG2 cells induced by microcystin-LR via mitochondria-mediated pathway. Chemosphere 157:241–249CrossRefPubMed Ma J, Feng Y, Liu Y, Li X (2016) PUMA and survivin are involved in the apoptosis of HepG2 cells induced by microcystin-LR via mitochondria-mediated pathway. Chemosphere 157:241–249CrossRefPubMed
48.
Metadaten
Titel
Antiproliferative activity of vitexin-2-O-xyloside and avenanthramides on CaCo-2 and HepG2 cancer cells occurs through apoptosis induction and reduction of pro-survival mechanisms
verfasst von
Emanuele Salvatore Scarpa
Elena Antonini
Francesco Palma
Michele Mari
Paolino Ninfali
Publikationsdatum
10.03.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nutrition / Ausgabe 4/2018
Print ISSN: 1436-6207
Elektronische ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-017-1418-y

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