An in vitro and in vivo investigation of the cytotoxic effects of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester and bortezomib in multiple myeloma cells

In this study, the in vitro and in vivo effectiveness of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) in combination with bortezomib, a proteasome inhibitor, was explored in multiple myeloma (MM) cells. Materials and methods: The cytotoxic effects of CAPE and bortezomib were determined by XTT cell proliferation assay. Apoptosis levels were analyzed with annexin V-fluorescein isothiocyanate, nuclear factor kappa beta (NF-kB) was analyzed with electrophoretic mobility-shift assay, and interleukin (IL)-6 levels were analyzed with enzyme-linked immunosorbent assay to evaluate CAPE's mechanism of action. To investigate the in vivo effectiveness of CAPE and bortezomib, an experimental plasmacytoma model was induced in BALB/c mice. Results: Increasing concentrations of CAPE and bortezomib decreased the proliferation of ARH-77 cells in a dose-dependent manner. With doses of CAPE IC50, a significant increase in apoptosis and a significant decrease in IL-6 levels were detected. The NF-kB DNA-binding activity decreased compared to the basal ARH-77 level. The administration of CAPE alone or in combination with bortezomib increased the rate of survival compared to the control group. Conclusion: We think that our study, which is the first to demonstrate the in vitro and in vivo effectiveness of the combined use of CAPE and bortezomib, will be a pioneer for future human applications of CAPE in MM.

An in vitro and in vivo investigation of the cytotoxic effects of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester and bortezomib in multiple myeloma cells

In this study, the in vitro and in vivo effectiveness of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) in combination with bortezomib, a proteasome inhibitor, was explored in multiple myeloma (MM) cells. Materials and methods: The cytotoxic effects of CAPE and bortezomib were determined by XTT cell proliferation assay. Apoptosis levels were analyzed with annexin V-fluorescein isothiocyanate, nuclear factor kappa beta (NF-kB) was analyzed with electrophoretic mobility-shift assay, and interleukin (IL)-6 levels were analyzed with enzyme-linked immunosorbent assay to evaluate CAPE's mechanism of action. To investigate the in vivo effectiveness of CAPE and bortezomib, an experimental plasmacytoma model was induced in BALB/c mice. Results: Increasing concentrations of CAPE and bortezomib decreased the proliferation of ARH-77 cells in a dose-dependent manner. With doses of CAPE IC50, a significant increase in apoptosis and a significant decrease in IL-6 levels were detected. The NF-kB DNA-binding activity decreased compared to the basal ARH-77 level. The administration of CAPE alone or in combination with bortezomib increased the rate of survival compared to the control group. Conclusion: We think that our study, which is the first to demonstrate the in vitro and in vivo effectiveness of the combined use of CAPE and bortezomib, will be a pioneer for future human applications of CAPE in MM.

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  • Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazón A, Azpilikueta A, Ochoa MC, Alfaro C et al. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 2008; 14: 6895–6906.
  • Gadó K, Silva S, Pálóczı K, Domján G, Falus A. Mouse plasmacytoma: an experimental model of human multiple myeloma. Haematologica 2001; 86: 227–236.
  • Pennisi A, Li X, Ling W, Khan S, Zangari M, Yaccoby S. The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am J Hematol 2009; 84: 6–14.
  • Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.
  • Campbell RA, Sanchez E, Steinberg J, Shalitin D, Li ZW, Chen H, Berenson JR. Vorinostat enhances the antimyeloma effects of melphalan and bortezomib. Eur J Haematol 2010; 84: 201–211.
  • Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351: 1860–1873.
  • Grunberger D, Banerjee R, Eisinger K, Oltz EM, Efros L, Caldwell M, Estevez V, Nakanishi K. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 1988; 44: 230–232.
  • Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: a breath of life or death? Clin Cancer Res 2007; 13: 789–794.
  • Orban Z, Mitsiades N, Burke TR Jr, Tsokos M, Chrousos GP. Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation 2000; 7: 99–105.
  • Nagaoka T, Banskota AH, Tezuka Y, Midorikawa K, Matsushige K, Kadota S. Caffeic acid phenethyl ester (CAPE) analogues: potent nitric oxide inhibitors from the Netherlands propolis. Biol Pharm Bull 2003; 26: 487–491.
  • Ilhan A, Iraz M, Gurel A, Armutcu F, Akyol O. Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochem Res 2004; 29: 2287–2292.
  • Durmuş M, Yılmaz HR, Uz E, Özçelik N. The effect of caffeic acid phenethyl ester (CAPE) treatment on levels of MDA, NO and antioxidant enzyme activities in retinas of streptozotocin- induced diabetic rats. Turk J Med Sci 2008; 38: 525–530.
  • Ara C, Dirican A, Erdoğan S, Ateş B, Özgör D, Tatlı F, Tekerekoğlu MS, Kırımlıoğlu V. The effect of caffeic acid phenethyl ester on bacterial translocation and intestinal damage after intestinal obstruction. Turk J Med Sci 2010; 40: 897–903.
  • Aydın E, Deniz Demir H, Özyurt H, Erkorkmaz Ü. Comparative efficacy of caffeic acid phenethyl ester (CAPE), olopatadine hydrochloride, and dexamethasone sodium phosphate in experimental allergic conjunctivitis. Turk J Med Sci 2010; 40: 605–612.
  • Hishikawa K, Nakaki T, Fujita T. Oral flavonoid supplementation attenuates atherosclerosis development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2005; 25: 442–446.
  • Lee KJ, Choi JH, Khanal T, Hwang YP, Chung YC, Jeong HG. Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. Toxicology 2008; 248: 18–24.
  • Chen YJ, Shiao MS, Wang SY. The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells. Anti-Cancer Drugs 2001; 12: 143–149.
  • Koru Ö, Avcu F, Tanyüksel M, Ural AU, Araz RE, Şener K. Cytotoxic effects of caffeic acid phenethyl ester (CAPE) on the human multiple myeloma cell line. Turk J Med Sci 2009; 39: 863–870.
  • Chen MF, Wu JC, Keng PC, Chen WC. Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells. J Radial Res 2004; 45: 253–260.
  • Huang MT, Ma W, Yen P. Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13- acetate-induced tumor promotion in mouse skin and synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis 1996; 17: 761–765.
  • Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood 1995; 85: 863–872.
  • Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto KI, Libermann TA, Anderson KC. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-κB. Blood 1996; 87: 1104–1112.
  • Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V et al. NF-κB as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.
  • Lu T, Sathe SS, Swiatkowski SM, Hampole CV, Stark GR. Secretion of cytokines and growth factors as a general cause of constitutive NF-κB activation in cancer. Oncogene 2004; 23: 2138–2145.
  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev Genes Dev 1995; 15; 9: 2723–2735.
  • Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest 2001; 107: 241–246.
  • Deng J, Miller SA, Wang HY, Xia W, Wen Y, Zhou BP, Li Y, Lin SY, Hung MC. Beta-catenin interacts with and inhibits NF- kappa B in human colon and breast cancer. Cancer Cell 2002; 2: 323–334.
  • Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE. Protein kinase CK2 promotes aberrant activation of nuclear factor-κB, transformed phenotype, and survival of breast cancer cells. Cancer Res 2002; 62: 6770–6778.
  • Ural AU, Yilmaz MI, Avcu F, Pekel A, Zerman M, Nevruz O, Sengul A, Yalcin A. The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide. Int J Hematol 2003; 78: 443–449.
  • You T, Hu W, Ge X, Shen J, Qin X. Application of a novel inhibitor of human CD59 for the enhancement of complement- dependent cytolysis on cancer cells. Cell Mol Immunol 2011; 8: 157–163.
  • Çoban ZD, Avcu F, Ural AU, Kuzhan O, Güran Ş. The sitotoxic effect of gemcitabine on multiple myeloma (RPMI-8226). and Ig G plasma cell leukemia (ARH 77) cell lines. Gülhane Tıp Derg 2012; 54: 263–266 (in Turkish with English abstract).
  • Avcu F, Ural AU, Yılmaz MI, Özcan A, İde T, Kurt B, Yalçın A. The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane. Eur J Haematol 2005; 74: 496–500.
  • Silva S, Sugiyama H, Babonits M, Wiener F, Klein G. Differential susceptibility of BALB/c and DBA/2 cells to plasmacytoma induction in reciprocal chimeras. Int J Cancer 1991; 49: 224– 228.
  • Lu T, Stark GR. Cytokine overexpression and constitutive NFκB in cancer. Cell Cycle 2004; 3: 1114–1117.
  • Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G, Maor-Aloni R, Kalis M, Levrero M, Strano S, Gorgoulis VG et al. Mutant p53 enhances nuclear factor κB activation by tumor necrosis factor a in cancer cells. Cancer Res 2007; 67: 2396– 2401.
  • Beg AA, Baltimore D. An essential role for NFκB in preventing TNF-a-induced cell death. Science 1996; 274: 782–784.
  • Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M, Kufe DW, Anderson KC. Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. Blood 1997; 89: 227–234.
  • Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K I, Libermann TA, Anderson KC. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996; 87: 1104–1112.
  • Onori P, DeMorrow S, Gaudio E, Franchitto A, Mancinelli R, Venter J, Kopriva S, Ueno, Y, Alvaro D, Savage J et al. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-κB and induction of apoptosis. Int J Cancer 2009; 125: 565–576.
  • McEleny K, Coffey R, Morrissey C, Fitzpatrick JM, Watson RW. Caffeic acid phenethyl ester-induced PC-3 cell apoptosis is caspase-dependent and mediated through the loss of inhibitors of apoptosis proteins. BJU Int 2004; 94: 402–406.
  • Watabe M, Hishikawa K, Takayanagi A, Shimizu N, Nakaki T. Caffeic acid phenethyl ester induces apoptosis by inhibition of NFκB and activation of Fas in human breast cancer MCF-7 cells. J Biol Chem 2004; 279: 6017–6026.
  • Borrelli F, Izzo AA, Di Carlo G, Maffia P, Russo A, Maiello FM, Capasso F, Mascolo N. Effect of a propolis extract and caffeic acid phenethyl ester on formation of aberrant crypt foci and tumors in the rat colon. Fitoterapia 2002; 73: 38–43.
  • Kimoto T, Koya S, Hino K, Yamamoto Y, Nomura Y, Micallef MJ, Hanaya T, Arai S, Ikeda M, Kurimoto M. Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C. Pathol Int 2000; 50: 679–689.
Turkish Journal of Medical Sciences-Cover
  • ISSN: 1300-0144
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

An in vitro and in vivo investigation of the cytotoxic effects of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester and bortezomib in multiple myeloma cells

Ertan ALTAYLI, Özgür KORU, Önder ÖNGÖRÜ, Tayfun İDE, Cengizhan AÇIKEL, Meral SARPER, Mualla Pınar ELÇİ, Rahşan ILIKÇI SAĞKAN, Erhan ASTARCI, Duran TOK, Salim ÖZENÇ, Ali Uğur URAL, Ferit AVCU

Clinicopathological importance of Ki-67, p27, and p53 expression in gastric cancer

Muhammet ÇALIK, Elif DEMİRCİ, Eren ALTUN, İlknur ÇALIK

Hypo- and hypervolemic edema in children with steroid sensitive nephrotic syndrome

Mehmet Akif BÜYÜKAVCI, Mahmut ÇİVİLİBAL, Murat ELEVLİ, Hatice Nilgün Selçuk DURU

Comparative study of virulence factors among ESβL-producing and nonproducing Pseudomonas aeruginosa clinical isolates

Fatma IBRAHIM SONBOL, Abdel Fattah Badr MOHAMED, Maha Abd El Fattah KHALIL, Sameh Samir ALI

Gastrointestinal system lesions in children due to the ingestion of alkali and acid corrosive substances

Kaan DEMİRÖREN, Halil KOCAMAZ, Yaşar DOĞAN

Analysis of vacA/cagA genotypes/status in Helicobacter pylori isolates from Iranian children and their association with clinical outcome

Tahereh FALSAFI, Afsaneh KHANI, Fatemeh MAHJOUB, Ezat ASGARANI, Nazli SOTOUDEH

Efficacy of entecavir treatment among chronic hepatitis B nucleos(t)ide-naïve and -experienced patients

Kadir Çağatay BİÇER, Alpay ARI, Vecdi Evren GENÇ, Sibel ÖZSU CAYMAZ, Meltem AVCI, Fatma BAL

Effects on quinolone resistance due to the biofilm formation activity in Ureaplasma urealyticum

Chunyan FENG, Ya HUANG, Yunsong YU, Guorong DUAN, Yuying DAI, Ke DONG, Qingtian LI

Is there any impact of PET/CT on radiotherapy planning in rectal cancer patients undergoing preoperative IMRT?

Diclehan KILIÇ, Serap ÇATLI, Şükran ÜLGER, Lütfiye Özlem KAPUCU

The effect of extracorporeal shock wave lithotripsy on distribution of interstitial cells of Cajal in rabbit renal pelvis and proximal ureter

Özlem BOYBEYİ, Mine Fedakar ŞENYÜCEL, Ebru Şebnem AYVA, Tutku SOYER, Mustafa Kemal ASLAN