Induction of apoptosis by a potent caffeic acid derivative, caffeic acid undecyl ester, is mediated by mitochondrial damage in NALM-6 human B cell leukemia cells

Tomizawa,Ayako; Kanno,Syu-ichi; Osanai,Yuu; Goto,Akane; Sato,Chizuru; Yomogida,Shin; Ishikawa,Masaaki

doi:10.3892/or.2012.2163

Induction of apoptosis by a potent caffeic acid derivative, caffeic acid undecyl ester, is mediated by mitochondrial damage in NALM-6 human B cell leukemia cells

Authors:
- Ayako Tomizawa
- Syu-ichi Kanno
- Yuu Osanai
- Akane Goto
- Chizuru Sato
- Shin Yomogida
- Masaaki Ishikawa
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Affiliations: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Sendai, Japan
Published online on: December 3, 2012 https://doi.org/10.3892/or.2012.2163
Pages: 425-429
Copyright: © Tomizawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Caffeic acid esters have various biological activities, and we previously reported that undecyl caffeate (caffeic acid undecyl ester, CAUE), a new caffeic acid derivative, has strong pharmacological activity. The present study investigated the cytotoxicity of both CAUE and its parent compound, caffeic acid phenethyl ester (CAPE), and characterized the mechanisms by which they induce apoptosis in the human B cell leukemia cell line NALM-6. Treatment with CAUE reduced cell survival in NALM-6 cells but had no significant effect on the survival of normal lymphocytes. When assessing the 50% inhibitory concentration (IC50) for cytotoxicity, CAUE had 10-fold higher activity than CAPE in NALM-6 cells. CAUE treatment resulted in induction of apoptotic features in NALM-6 cells, including cleaved poly (ADP-ribose) polymerase and activated caspase-3. A caspase inhibitor completely blocked CAUE-induced apoptosis. CAUE treatment resulted in a concentration- and time-dependent decrease in both mitochondrial membrane potential and downregulation of Bcl-2 expression. Moreover, CAUE-induced apoptosis was enhanced in the Bcl-2 knockdown condition induced by small interfering RNA. These data suggest that CAUE-induced apoptosis was mediated via an apoptotic intrinsic pathway including mitochondrial damage and was caspase-dependent. These data also suggest that CAUE is a powerful anti-leukemic agent that acts via induction of apoptosis by mitochondrial damage and selective action in leukemia cells.

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1	Banskota AH, Tezuka Y, Midorikawa K, Matsushige K and Kadota S: Two novel cytotoxic benzofuran derivatives from Brazilian propolis. J Nat Prod. 63:1277–1279. 2000. View Article : Google Scholar : PubMed/NCBI
2	Burdock GA: Review of the biological properties and toxicity of bee propolis (propolis). Food Chem Toxicol. 36:347–363. 1998. View Article : Google Scholar : PubMed/NCBI
3	Banskota AH, Nagaoka T, Sumioka LY, et al: Antiproliferative activity of the Netherlands propolis and its active principles in cancer cell lines. J Ethnopharmacol. 80:67–73. 2002. View Article : Google Scholar : PubMed/NCBI
4	Watanabe MA, Amarante MK, Conti BJ and Sforcin JM: Cytotoxic constituents of propolis inducing anticancer effects: a review. J Pharm Pharmacol. 63:1378–1386. 2011. View Article : Google Scholar : PubMed/NCBI
5	Lee YJ, Kuo HC, Chu CY, Wang CJ, Lin WC and Tseng TH: Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells. Biochem Pharmacol. 66:2281–2289. 2003. View Article : Google Scholar : PubMed/NCBI
6	Jin UH, Song KH, Motomura M, et al: Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. Mol Cell Biochem. 310:43–48. 2008. View Article : Google Scholar : PubMed/NCBI
7	Gupta S, Kass GE, Szegezdi E and Joseph B: The mitochondrial death pathway: a promising therapeutic target in diseases. J Cell Mol Med. 13:1004–1033. 2009. View Article : Google Scholar : PubMed/NCBI
8	Kim R, Emi M, Tanabe K and Toge T: Therapeutic potential of antisense Bcl-2 as a chemosensitizer for cancer therapy. Cancer. 101:2491–2502. 2004. View Article : Google Scholar : PubMed/NCBI
9	Ujibe M, Kanno S, Osanai Y, et al: Octylcaffeate induced apoptosis in human leukemia U937 cells. Biol Pharm Bull. 28:2338–2341. 2005. View Article : Google Scholar : PubMed/NCBI
10	Uwai K, Osanai Y, Imaizumi T, Kanno S, Takeshita M and Ishikawa M: Inhibitory effect of the alkyl side chain of caffeic acid analogues on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages. Bioorg Med Chem. 16:7795–7803. 2008. View Article : Google Scholar : PubMed/NCBI
11	Kanno S, Maeda N, Tomizawa A, Yomogida S, Katoh T and Ishikawa M: Involvement of p21^waf1/cip1 expression in the cytotoxicity of the potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells. Int J Oncol. 40:1391–1396. 2012.
12	Watanabe K, Kanno S, Tomizawa A, Yomogida S and Ishikawa M: Acacetin induces apoptosis in human T cell leukemia Jurkat cells via activation of a caspase cascade. Oncol Rep. 27:204–209. 2012.PubMed/NCBI
13	Kanno S, Higurashi A, Watanabe Y, Shouji A, Asou K and Ishikawa M: Susceptibility to cytosine arabinoside (Ara-C)-induced cytotoxicity in human leukemia cell lines. Toxicol Lett. 152:149–158. 2004.PubMed/NCBI
14	Cortelazzo S, Ponzoni M, Ferreri AJ and Hoelzer D: Lymphoblastic lymphoma. Crit Rev Oncol Hematol. 79:330–343. 2011. View Article : Google Scholar
15	Hurwitz R, Hozier J, LeBien T, et al: Characterization of a leukemic cell line of the pre-B phenotype. Int J Cancer. 23:174–180. 1979. View Article : Google Scholar : PubMed/NCBI
16	Grunberger D, Banerjee R, Eisinger K, et al: Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia. 44:230–232. 1988. View Article : Google Scholar : PubMed/NCBI
17	Najafi MF, Vahedy F, Seyyedin M, Jomehzadeh HR and Bozary K: Effect of the water extracts of propolis on stimulation and inhibition of different cells. Cytotechnology. 54:49–56. 2007. View Article : Google Scholar : PubMed/NCBI
18	Kaufmann SH and Vaux DL: Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene. 22:7414–7430. 2003. View Article : Google Scholar : PubMed/NCBI
19	Boatright KM and Salvesen GS: Mechanisms of caspase activation. Curr Opin Cell Biol. 15:725–731. 2003. View Article : Google Scholar : PubMed/NCBI
20	Satoh MS and Lindahl T: Role of poly(ADP-ribose) formation in DNA repair. Nature. 356:356–358. 1992. View Article : Google Scholar : PubMed/NCBI
21	Tewari M, Quan LT, O’Rourke K, et al: Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 81:801–809. 1995. View Article : Google Scholar : PubMed/NCBI
22	Cheson BD: Oblimersen for the treatment of patients with chronic lymphocytic leukemia. Ther Clin Risk Manag. 3:855–870. 2007.PubMed/NCBI
23	Vogler M, Dinsdale D, Dyer MJ and Cohen GM: Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ. 16:360–367. 2009. View Article : Google Scholar : PubMed/NCBI