Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

Author(s): Ali Hassanzadeh, Adel Naimi, Majid F. Hagh, Raedeh Saraei, Faroogh Marofi, Saeed Solali*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 15 , 2019

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Graphical Abstract:


Abstract:

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the Tumor Necrosis Factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells through binding to Death Receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently, its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL through different pathways. TRAIL plus kaempferol was used to eliminate the resistance of the MOLT-4 cells to TRAIL.

Materials and Methods: Firstly, IC50 for kaempferol (95μM) was determined by using the MTT assay. Secondly, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100nM) and kaempferol (95μM) alone and in combination. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique.

Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, it was found that kaempferol could inhibit the expression of c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment the expression of DR4/5 in MOLT-4 cells.

Conclusion: It is suggested that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL by inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

Keywords: Acute Lymphoblastic Leukemia (ALL), MOLT-4, kaempferol, resistance, TRAIL, VEGF.

[1]
Fasal, E.; Jackson, E.W.; Klauber, M.R. Leukemia and lymphoma mortality and farm residence. Am. J. Epidemiol., 1968, 87(2), 267-274.
[2]
Inaba, H.; Greaves, M.; Mullighan, C.G. Acute lymphoblastic leukaemia. Lancet, 2013, 381(9881), 1943-1955.
[3]
Küley-Bagheri, Y.; Kreuzer, K.A.; Monsef, I.; Lübbert, M.; Skoetz, N. Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL)). Cochrane Database Syst. Rev., 2018, 8CD011960
[4]
Chellapandian, D.; Pole, J.D.; Nathan, P.C.; Sung, L. Congestive heart failure among children with acute leukemia: A population-based matched cohort study. Leuk. Lymphoma, 2018, 60(2), 385-394.
[5]
Giebel, S.; Marks, D.I.; Boissel, N.; Baron, F.; Chiaretti, S.; Ciceri, F. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: A position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant., 2018, 54(6), 798-809.
[6]
Nazim, U.M.; Moon, J.H.; Lee, J.H.; Lee, Y.J.; Seol, J.W.; Eo, S.K.; Lee, J.H.; Park, S.Y. Activation of autophagy flux by metformin downregulates cellular FLICE-like inhibitory protein and enhances TRAIL- induced apoptosis. Oncotarget, 2016, 7(17), 23468-23481.
[7]
Linderoth, E.; Pilia, G.; Mahajan, N.P.; Ferby, I. Activated Cdc42-associated kinase 1 (Ack1) is required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor recruitment to lipid rafts and induction of cell death. J. Biol. Chem., 2013, 288(46), 32922-32931.
[8]
Raulf, N.; El-Attar, R.; Kulms, D.; Lecis, D.; Delia, D.; Walczak, H.; Papenfuss, K.; Odell, E.; Tavassoli, M. Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10. Br. J. Cancer, 2014, 111(10), 1955-1964.
[9]
Allen, J.E.; El-Deiry, W.S. Regulation of the human TRAIL gene. Cancer Biol. Ther., 2012, 13(12), 1143-1151.
[10]
Tazzari, P.L.; Tabellini, G.; Ricci, F.; Papa, V.; Bortul, R.; Chiarini, F.; Evangelisti, C.; Martinelli, G.; Bontadini, A.; Cocco, L.; McCubrey, J.A.; Martelli, A.M. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res., 2008, 68(22), 9394-9403.
[11]
Altucci, L.; Rossin, A.; Raffelsberger, W.; Reitmair, A.; Chomienne, C.; Gronemeyer, H. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat. Med., 2001, 7(6), 680-686.
[12]
Altucci, L.; Rossin, A.; Hirsch, O.; Nebbioso, A.; Vitoux, D.; Wilhelm, E.; Guidez, F.; De Simone, M.; Schiavone, E.M.; Grimwade, D.; Zelent, A.; de Thé, H.; Gronemeyer, H. Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res., 2005, 65(19), 8754-8765.
[13]
Nieda, M.; Nicol, A.; Koezuka, Y.; Kikuchi, A.; Lapteva, N.; Tanaka, Y.; Tokunaga, K.; Suzuki, K.; Kayagaki, N.; Yagita, H.; Hirai, H.; Juji, T. TRAIL expression by activated human CD4(+)V alpha 24NKT cells induces in vitro and in vivo apoptosis of human acute myeloid leukemia cells. Blood, 2001, 97(7), 2067-2074.
[14]
Cretney, E.; Shanker, A.; Yagita, H.; Smyth, M.J.; Sayers, T.J. TNF-related apoptosis-inducing ligand as a therapeutic agent in autoimmunity and cancer. Immunol. Cell Biol., 2006, 84(1), 87-98.
[15]
Shi, J.; Zheng, D.; Man, K.; Fan, S.T.; Xu, R. TRAIL: A potential agent for cancer therapy. Curr. Mol. Med., 2003, 3(8), 727-736.
[16]
Almasan, A.; Ashkenazi, A. Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev., 2003, 14(3-4), 337-348.
[17]
von Karstedt, S.; Montinaro, A.; Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer, 2017, 17(6), 352-366.
[18]
Ahn, D.S.; Lee, H.J.; Hwang, J.; Han, H.; Kim, B.; Shim, B.; Kim, S.H. Lambertianic acid sensitizes non-small cell lung cancers to TRAIL-induced apoptosis via inhibition of XIAP/NF-κB and activation of caspases and death receptor 4. Int. J. Mol. Sci., 2018, 19(5)E1476
[19]
Finlay, D.; Vamos, M.; González-López, M.; Ardecky, R.J.; Ganji, S.R.; Yuan, H.; Su, Y.; Cooley, T.R.; Hauser, C.T.; Welsh, K.; Reed, J.C.; Cosford, N.D.; Vuori, K. Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: Roles of XIAP and cIAPs. Mol. Cancer Ther., 2014, 13(1), 5-15.
[20]
Guicciardi, M.E.; Mott, J.L.; Bronk, S.F.; Kurita, S.; Fingas, C.D.; Gores, G.J. Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Exp. Cell Res., 2011, 317(1), 107-116.
[21]
Huang, Y.; Yang, X.; Xu, T.; Kong, Q.; Zhang, Y.; Shen, Y.; Wei, Y.; Wang, G.; Chang, K.J. Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. Int. J. Oncol., 2016, 49(1), 153-163.
[22]
Geismann, C.; Grohmann, F.; Dreher, A.; Häsler, R.; Rosenstiel, P.; Legler, K.; Hauser, C.; Egberts, J.H.; Sipos, B.; Schreiber, S.; Linkermann, A.; Hassan, Z.; Schneider, G.; Schäfer, H.; Arlt, A. Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer. Biochim. Biophys. Acta Mol. Cell Res., 2017, 1864(5), 782-796.
[23]
Mohamed, M.S.; Bishr, M.K.; Almutairi, F.M.; Ali, A.G. Inhibitors of apoptosis: Clinical implications in cancer. Apoptosis, 2017, 22(12), 1487-1509.
[24]
Hofer-Warbinek, R.; Schmid, J.A.; Stehlik, C.; Binder, B.R.; Lipp, J.; de Martin, R. Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1. J. Biol. Chem., 2000, 275(29), 22064-22068.
[25]
Levkau, B.; Garton, K.J.; Ferri, N.; Kloke, K.; Nofer, J.R.; Baba, H.A.; Raines, E.W.; Breithardt, G. xIAP induces cell-cycle arrest and activates nuclear factor-kappaB: New survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells. Circ. Res., 2001, 88(3), 282-290.
[26]
Chae, Y.K.; Ranganath, K.; Hammerman, P.S.; Vaklavas, C.; Mohindra, N.; Kalyan, A.; Matsangou, M.; Costa, R.; Carneiro, B.; Villaflor, V.M.; Cristofanilli, M.; Giles, F.J. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: The current landscape and barriers to clinical application. Oncotarget, 2017, 8(9), 16052-16074.
[27]
Shankar, S.; Ganapathy, S.; Chen, Q.; Srivastava, R.K. Curcumin sensitizes TRAIL-resistant xenografts: Molecular mechanisms of apoptosis, metastasis and angiogenesis. Mol. Cancer, 2008, 7(1), 16.
[28]
Kim, N. Butein sensitizes human leukemia cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Arch. Pharm. Res., 2008, 31(9), 1179-1186.
[29]
Szliszka, E.; Krol, W. Polyphenols isolated from propolis augment TRAIL-induced apoptosis in cancer cells. Evid. Based Complement. Alternat. Med., 2013, 2013731940
[30]
Szliszka, E.; Zydowicz, G.; Janoszka, B.; Dobosz, C.; Kowalczyk-Ziomek, G.; Krol, W. Ethanolic extract of Brazilian green propolis sensitizes prostate cancer cells to TRAIL-induced apoptosis. Int. J. Oncol., 2011, 38(4), 941-953.
[31]
Toume, K.; Habu, T.; Arai, M.A.; Koyano, T.; Kowithayakorn, T.; Ishibashi, M. Prenylated flavonoids and resveratrol derivatives isolated from Artocarpus communis with the ability to overcome TRAIL resistance. J. Nat. Prod., 2015, 78(1), 103-110.
[32]
Dang, Q.; Song, W.; Xu, D.; Ma, Y.; Li, F.; Zeng, J.; Zhu, G.; Wang, X.; Chang, L.S.; He, D.; Li, L. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis. Mol. Carcinog., 2015, 54(9), 831-840.
[33]
Choi, E.J.; Ahn, W.S. Kaempferol induced the apoptosis via cell cycle arrest in human breast cancer MDA-MB-453 cells. Nutr. Res. Pract., 2008, 2(4), 322-325.
[34]
Leardkamolkarn, V.; Tiamyuyen, S.; Sripanidkulchai, B.O. Pharmacological activity of Kaempferia parviflora extract against human bile duct cancer cell lines. Asian Pac. J. Cancer Prev., 2009, 10(4), 695-698.
[35]
Mylonis, I.; Lakka, A.; Tsakalof, A.; Simos, G. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions. Biochem. Biophys. Res. Commun., 2010, 398(1), 74-78.
[36]
Song, H.; Bao, J.; Wei, Y.; Chen, Y.; Mao, X.; Li, J.; Yang, Z.; Xue, Y. Kaempferol inhibits gastric cancer tumor growth: An in vitro and in vivo study. Oncol. Rep., 2015, 33(2), 868-874.
[37]
Song, W.; Dang, Q.; Xu, D.; Chen, Y.; Zhu, G.; Wu, K.; Zeng, J.; Long, Q.; Wang, X.; He, D.; Li, L. Kaempferol induces cell cycle arrest and apoptosis in renal cell carcinoma through EGFR/p38 signaling. Oncol. Rep., 2014, 31(3), 1350-1356.
[38]
Yoshida, T.; Konishi, M.; Horinaka, M.; Yasuda, T.; Goda, A.E.; Taniguchi, H.; Yano, K.; Wakada, M.; Sakai, T. Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis. Biochem. Biophys. Res. Commun., 2008, 375(1), 129-133.
[39]
Siegelin, M.D.; Reuss, D.E.; Habel, A.; Herold-Mende, C.; von Deimling, A. The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin. Mol. Cancer Ther., 2008, 7(11), 3566-3574.
[40]
Basu, A.; Das, A.S.; Sharma, M.; Pathak, M.P.; Chattopadhyay, P.; Biswas, K.; Mukhopadhyay, R. STAT3 and NF-κB are common targets for kaempferol-mediated attenuation of COX-2 expression in IL-6-induced macrophages and carrageenan-induced mouse paw edema. Biochem. Biophys. Rep., 2017, 12, 54-61.
[41]
Luo, H.; Rankin, G.O.; Liu, L.; Daddysman, M.K.; Jiang, B.H.; Chen, Y.C. Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr. Cancer, 2009, 61(4), 554-563.
[42]
Li, S.; Payne, S.; Wang, F.; Claus, P.; Su, Z.; Groth, J.; Geradts, J.; de Ridder, G.; Alvarez, R.; Marcom, P.K.; Pizzo, S.V.; Bachelder, R.E. Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance. Breast Cancer Res., 2015, 17(1), 91.
[43]
Nusrat, O.; Belotte, J.; Fletcher, N.M.; Memaj, I.; Saed, M.G.; Diamond, M.P.; Saed, G.M. The role of angiogenesis in the persistence of chemoresistance in epithelial ovarian cancer. Reprod. Sci., 2016, 23(11), 1484-1492.
[44]
Brunetti, G.; Di Benedetto, A.; Posa, F.; Colaianni, G.; Faienza, M.F.; Ballini, A.; Colucci, S.; Passeri, G.; Lo Muzio, L.; Grano, M.; Mori, G. High expression of TRAIL by osteoblastic differentiated dental pulp stem cells affects myeloma cell viability. Oncol. Rep., 2018, 39(4), 2031-2039.
[45]
Falschlehner, C.; Emmerich, C.H.; Gerlach, B.; Walczak, H. TRAIL signalling: Decisions between life and death. Int. J. Biochem. Cell Biol., 2007, 39(7-8), 1462-1475.
[46]
Guiho, R.; Biteau, K.; Heymann, D.; Redini, F. TRAIL-based therapy in pediatric bone tumors: How to overcome resistance. Future Oncol., 2015, 11(3), 535-542.
[47]
Yang, L.; Wang, Q.; Li, D.; Zhou, Y.; Zheng, X.; Sun, H.; Yan, J.; Zhang, L.; Lin, Y.; Wang, X. Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIPL and IAP proteins. Apoptosis, 2013, 18(5), 618-626.
[48]
Bellail, A.C.; Qi, L.; Mulligan, P.; Chhabra, V.; Hao, C. TRAIL agonists on clinical trials for cancer therapy: The promises and the challenges. Rev. Recent Clin. Trials, 2009, 4(1), 34-41.
[49]
Yuan, X.; Gajan, A.; Chu, Q.; Xiong, H.; Wu, K.; Wu, G.S. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev., 2018, 37(4), 733-748.
[50]
Lim, B.; Allen, J.E.; Prabhu, V.V.; Talekar, M.K.; Finnberg, N.K.; El-Deiry, W.S. Targeting TRAIL in the treatment of cancer: New developments. Expert Opin. Ther. Targets, 2015, 19(9), 1171-1185.
[51]
Day, T.W.; Huang, S.; Safa, A.R. c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells. Biochem. Pharmacol., 2008, 76(12), 1694-1704.
[52]
Saraei, R.; Soleimani, M.; Movassaghpour Akbari, A.A.; Farshdousti Hagh, M.; Hassanzadeh, A.; Solali, S. The role of XIAP in resistance to TNF-related apoptosis-inducing ligand (TRAIL) in Leukemia. Biomed. Pharmacother., 2018, 107, 1010-1019.
[53]
Hassanzadeh, A.; Farshdousti Hagh, M.; Alivand, M.R.; Akbari, A.A.M.; Shams Asenjan, K.; Saraei, R.; Solali, S. Down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL. J. Cell. Physiol., 2018, 233(10), 6470-6485.
[54]
Alkurdi, L.; Virard, F.; Vanbervliet, B.; Weber, K.; Toscano, F.; Bonnin, M.; Le Stang, N.; Lantuejoul, S.; Micheau, O.; Renno, T.; Lebecque, S.; Estornes, Y. Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis. Cell Death Dis., 2018, 9(9), 874.
[55]
Chang, L.; Kamata, H.; Solinas, G.; Luo, J-L.; Maeda, S.; Venuprasad, K.; Liu, Y.C.; Karin, M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turn over. Cell, 2006, 124(3), 601-613.
[56]
Kaminskyy, V.O.; Surova, O.V.; Piskunova, T.; Zborovskaya, I.B.; Tchevkina, E.M.; Andera, L.; Zhivotovsky, B. Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling. Cell Death Dis., 2013, 4e, 522.
[57]
Kaplan-Lefko, P.J.; Graves, J.D.; Zoog, S.J.; Pan, Y.; Wall, J.; Branstetter, D.G.; Moriguchi, J.; Coxon, A.; Huard, J.N.; Xu, R.; Peach, M.L.; Juan, G.; Kaufman, S.; Chen, Q.; Bianchi, A.; Kordich, J.J.; Ma, M.; Foltz, I.N.; Gliniak, B.C. Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol. Ther., 2010, 9(8), 618-631.
[58]
Gottwald, L.; Piekarski, J.; Kubiak, R.; Szwalski, J.; Pasz-Walczak, G.; Sęk, P.; Spych, M.; Suzin, J.; Tyliński, W.; Jeziorski, A. Membrane expression of TRAIL receptors DR4, DR5, DcR1 and DcR2 in the normal endometrium, atypical endometrial hyperplasia and endometrioid adenocarcinoma: A tissue microarray study. Arch. Gynecol. Obstet., 2013, 288(4), 889-899.
[59]
Lee, Y.S.; Lee, D.H.; Jeong, S.Y.; Park, S.H.; Oh, S.C.; Park, Y.S. Ferroptosis-inducing agents enhance TRAIL-induced apoptosis through upregulation of death receptor 5. J. Cell. Biochem., 2018, 120(1), 928-939.
[60]
Son, B.; Lee, S.; Youn, H.; Kim, E.; Kim, W.; Youn, B. The role of tumor microenvironment in therapeutic resistance. Oncotarget, 2017, 8(3), 3933-3945.
[61]
Presta, M.; Chiodelli, P.; Giacomini, A.; Rusnati, M.; Ronca, R. Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach. Pharmacol. Ther., 2017, 179, 171-187.
[62]
Wagner, J.; Kline, C.L.; Zhou, L.; Khazak, V.; El-Deiry, W.S. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J. Exp. Clin. Cancer Res., 2018, 37(1), 11.
[63]
Abou El Naga, R.N.; Azab, S.S.; El-Demerdash, E.; Shaarawy, S.; El-Merzabani, M.; Ammar, S.M. Sensitization of TRAIL-induced apoptosis in human hepatocellular carcinoma HepG2 cells by phytochemicals. Life Sci., 2013, 92(10), 555-561.
[64]
Zhuang, Z.; Ye, G.; Huang, B. Kaempferol Alleviates the Interleukin-1β-Induced Inflammation in Rat Osteoarthritis Chondrocytes via Suppression of NF-κB. Med. Sci. Monit., 2017, 23, 3925-3931.
[65]
Zhao, Y.; Tian, B.; Wang, Y.; Ding, H. Kaempferol sensitizes human ovarian cancer cells-OVCAR-3 and SKOV-3 to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis via JNK/ERK-CHOP pathway and up-regulation of death receptors 4 and 5. Med. Sci. Monit., 2017, 23, 5096-5105.
[66]
Wu, Y.; Zhang, Q.; Zhang, R. Kaempferol targets estrogen-related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions. Exp. Ther. Med., 2017, 14(6), 5576-5582.
[67]
Havsteen, B.H. The biochemistry and medical significance of the flavonoids. Pharmacol. Ther., 2002, 96(2-3), 67-202.
[68]
Chen, A.Y.; Chen, Y.C. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem., 2013, 138(4), 2099-2107.
[69]
Darband, S.G.; Kaviani, M.; Yousefi, B.; Sadighparvar, S.; Pakdel, F.G.; Attari, J.A.; Mohebbi, I.; Naderi, S.; Majidinia, M. Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. J. Cell. Physiol., 2018, 233(9), 6544-6560.
[70]
Gatouillat, G.; Magid, A.A.; Bertin, E. El btaouri, H.; Morjani, H.; Lavaud, C.; Madoulet, C. Medicarpin and millepurpan, two flavonoids isolated from Medicago sativa, induce apoptosis and overcome multidrug resistance in leukemia P388 cells. Phytomedicine, 2015, 22(13), 1186-1194.
[71]
Ikegawa, T.; Ohtani, H.; Koyabu, N.; Juichi, M.; Iwase, Y.; Ito, C.; Furukawa, H.; Naito, M.; Tsuruo, T.; Sawada, Y. Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Cancer Lett., 2002, 177(1), 89-93.
[72]
Teles, Y.C.F.; Souza, M.S.R.; Souza, M.F.V. Sulphated flavonoids: Biosynthesis, structures, and biological activities. Molecules, 2018, 23(2), 480.


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VOLUME: 19
ISSUE: 15
Year: 2019
Page: [1835 - 1845]
Pages: 11
DOI: 10.2174/1871520619666190731155859
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