CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation

Fang,Zhenghuan; Jung,Kyung  Hee; Yan,Hong  Hua; Kim,Soo  Jung; Son,Mi  Kwon; Rumman,Marufa; Lee,Hyunseung; Kim,Ki  Woon; Yoo,Hye-Dong; Hong,Soon-Sun

doi:10.3892/ijo.2015.2994

CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation

Authors:
- Zhenghuan Fang
- Kyung Hee Jung
- Hong Hua Yan
- Soo Jung Kim
- Mi Kwon Son
- Marufa Rumman
- Hyunseung Lee
- Ki Woon Kim
- Hye-Dong Yoo
- Soon-Sun Hong
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Affiliations: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea, Chodang Pharmaceutical Research Institute, Seoul 152-860, Republic of Korea
Published online on: May 11, 2015 https://doi.org/10.3892/ijo.2015.2994
Pages: 253-261

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Abstract

Chronic myeloid leukemia (CML) is characterized by a constitutively active Bcr-Abl tyrosine kinase. Although Imatinib has been proven to be an effective drug against CML, its resistance has been observed with disease relapse due to T315I predominant point mutation. Liriodendron tulipifera L., one of the fastest growing hardwood tree species, exerts antioxidant activity and anti-inflammatory effects. However, its anticancer effect has been minimally reported. In this study, we extracted CD-200 from Liriodendron tulipifera L. and investigated its effect on cell survival or apoptosis in CML cells with Bcr-Abl/T315I (BaF3/T315I) as well as wild-type Bcr-Abl (BaF3/WT). CD-200 inhibited cell proliferation in the BaF3/WT cells, and also in the BaF3/T315I cells with Imatinib resistance. Moreover, it strongly inhibited Bcr-Abl signaling pathways in a dose-dependent manner. Also, it significantly increased the sub-G1 phase and the expression of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we observed that CD-200 induced apoptosis with a loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin. Furthermore, CD-200 showed a significant inhibition in tumor growth, compared to Imatinib in BaF3/T315I mouse xenograft models. Taken together, our study demonstrates that CD-200 exhibits apoptosis induction and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the Bcr-Abl/T315I with resistance to Imatinib. We suggest that CD-200 may be a natural product to target Bcr-Abl and overcome Imatinib resistance in CML patients.

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1	Savona M and Talpaz M: Chronic myeloid leukemia: changing the treatment paradigms. Oncology (Williston Park). 20:707–711; discussion 712–704, 719, 724. 2006.
2	Huang X, Cortes J and Kantarjian H: Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer. 118:3123–3127. 2012. View Article : Google Scholar : PubMed/NCBI
3	Kurzrock R, Gutterman JU and Talpaz M: The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 319:990–998. 1988. View Article : Google Scholar : PubMed/NCBI
4	Tomoda K, Kato JY, Tatsumi E, Takahashi T, Matsuo Y and Yoneda-Kato N: The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression. Blood. 105:775–783. 2005. View Article : Google Scholar
5	Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 344:1031–1037. 2001. View Article : Google Scholar : PubMed/NCBI
6	Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 355:2408–2417. 2006. View Article : Google Scholar : PubMed/NCBI
7	Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J and Sawyers CL: Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2:117–125. 2002. View Article : Google Scholar : PubMed/NCBI
8	Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN and Sawyers CL: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 293:876–880. 2001. View Article : Google Scholar : PubMed/NCBI
9	Al-Achkar W, Wafa A, Moassass F, Klein E and Liehr T: Multiple copies of BCR-ABL fusion gene on two isodicentric Philadelphia chromosomes in an imatinib mesylate-resistant chronic myeloid leukemia patient. Oncol Lett. 5:1579–1582. 2013.PubMed/NCBI
10	Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, et al: Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 16:2190–2196. 2002. View Article : Google Scholar : PubMed/NCBI
11	O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, et al: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 65:4500–4505. 2005. View Article : Google Scholar
12	Martinelli G, Iacobucci I, Soverini S, Palandri F, Castagnetti F, Rosti G and Baccarani M: Nilotinib: A novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance. Biologics. 1:121–127. 2007.PubMed/NCBI
13	Shah NP, Tran C, Lee FY, Chen P, Norris D and Sawyers CL: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 305:399–401. 2004. View Article : Google Scholar : PubMed/NCBI
14	Goh SS, Woodman OL, Pepe S, Cao AH, Qin C and Ritchie RH: The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms. Antioxid Redox Signal. 9:101–113. 2007. View Article : Google Scholar
15	Winkelmann I, Diehl D, Oesterle D, Daniel H and Wenzel U: The suppression of aberrant crypt multiplicity in colonic tissue of 1,2-dimethylhydrazine-treated C57BL/6J mice by dietary flavone is associated with an increased expression of Krebs cycle enzymes. Carcinogenesis. 28:1446–1454. 2007. View Article : Google Scholar : PubMed/NCBI
16	Lafon CW: Stand dynamics of a yellow-poplar (Liriodendron tulipifera L.) forest in the Appalachian Mountains, Virginia, USA. Dendrochronologia. 22:43–52. 2004. View Article : Google Scholar
17	Rafinesque CS: Medical Flora or Manual of the Medical Botany of the United States of North America. In two volumes. Philadelphia: 1828
18	Graziose R, Rathinasabapathy T, Lategan C, Poulev A, Smith PJ, Grace M, Lila MA and Raskin I: Antiplasmodial activity of aporphine alkaloids and sesquiterpene lactones from Liriodendron tulipifera L. J Ethnopharmacol. 133:26–30. 2011. View Article : Google Scholar
19	Li WJ, Lin YC, Wu PF, Wen ZH, Liu PL, Chen CY and Wang HM: Biofunctional constituents from Liriodendron tulipifera with antioxidants and anti-melanogenic properties. Int J Mol Sci. 14:1698–1712. 2013. View Article : Google Scholar : PubMed/NCBI
20	Doskotch RW and el-Feraly FS: Antitumor agents. II Tulipinolide, a new germacranolide sesquiterpene, and constunolide Two cytotoxic substances from Liriodendron tulipifera L. J Pharm Sci. 58:877–880. 1969. View Article : Google Scholar : PubMed/NCBI
21	Moon MK, Oh HM, Kwon BM, Baek NI, Kim SH, Kim JS and Kim DK: Farnesyl protein transferase and tumor cell growth inhibitory activities of lipiferolide isolated from Liriodendron tulipifera. Arch Pharm Res. 30:299–302. 2007. View Article : Google Scholar : PubMed/NCBI
22	Neelakantan S, Nasim S, Guzman ML, Jordan CT and Crooks PA: Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-kappaB inhibitor, DMAPT (LC-1). Bioorg Med Chem Lett. 19:4346–4349. 2009. View Article : Google Scholar : PubMed/NCBI
23	Kaufmann SH and Hengartner MO: Programmed cell death: Alive and well in the new millennium. Trends Cell Biol. 11:526–534. 2001. View Article : Google Scholar : PubMed/NCBI
24	Kinghorn AD, Chin YW and Swanson SM: Discovery of natural product anticancer agents from biodiverse organisms. Curr Opin Drug Discov Devel. 12:189–196. 2009.PubMed/NCBI
25	Balunas MJ, Su B, Landini S, Brueggemeier RW and Kinghorn AD: Interference by naturally occurring fatty acids in a noncellular enzyme-based aromatase bioassay. J Nat Prod. 69:700–703. 2006. View Article : Google Scholar : PubMed/NCBI
26	Zhao J: Nutraceuticals, nutritional therapy, phytonutrients, and phytotherapy for improvement of human health: A perspective on plant biotechnology application. Recent Pat Biotechnol. 1:75–97. 2007. View Article : Google Scholar : PubMed/NCBI
27	Hong SW, Jung KH, Lee HS, Choi MJ, Son MK, Zheng HM and Hong SS: SB365 inhibits angiogenesis and induces apoptosis of hepatocellular carcinoma through modulation of PI3K/Akt/mTOR signaling pathway. Cancer Sci. 103:1929–1937. 2012. View Article : Google Scholar : PubMed/NCBI
28	de Oliveira LZ, Farias IL, Rigo ML, Glanzner WG, Gonçalves PB, Cadoná FC, Cruz IB, Farias JG, Duarte MM, Franco L, et al: Effect of Uncaria tomentosa extract on apoptosis triggered by oxaliplatin exposure on HT29 cells. Evid Based Complement Alternat Med. 2014:2747862014. View Article : Google Scholar : PubMed/NCBI
29	Deininger M, Buchdunger E and Druker BJ: The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 105:2640–2653. 2005. View Article : Google Scholar
30	O’Hare T, Corbin AS and Druker BJ: Targeted CML therapy: Controlling drug resistance, seeking cure. Curr Opin Genet Dev. 16:92–99. 2006. View Article : Google Scholar
31	Jabbour E, Cortes J and Kantarjian H: Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review. Core Evid. 4:207–213. 2009. View Article : Google Scholar
32	Quintás-Cardama A, Kantarjian H and Cortes J: Flying under the radar: The new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 6:834–848. 2007. View Article : Google Scholar : PubMed/NCBI
33	Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE and McCubrey JA: JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 18:189–218. 2004. View Article : Google Scholar : PubMed/NCBI
34	Kirchner D, Duyster J, Ottmann O, Schmid RM, Bergmann L and Munzert G: Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol. 31:504–511. 2003. View Article : Google Scholar : PubMed/NCBI
35	Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE and Skorski T: The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 21:5766–5774. 2002. View Article : Google Scholar : PubMed/NCBI
36	Hemmeryckx B, van Wijk A, Reichert A, Kaartinen V, de Jong R, Pattengale PK, Gonzalez-Gomez I, Groffen J and Heisterkamp N: Crkl enhances leukemogenesis in BCR/ABL P190 transgenic mice. Cancer Res. 61:1398–1405. 2001.PubMed/NCBI
37	Hoelbl A, Schuster C, Kovacic B, Zhu B, Wickre M, Hoelzl MA, Fajmann S, Grebien F, Warsch W, Stengl G, et al: Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol Med. 2:98–110. 2010. View Article : Google Scholar : PubMed/NCBI
38	Cabot MC, Giuliano AE, Han TY and Liu YY: SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells. Cancer Res. 59:880–885. 1999.PubMed/NCBI
39	Selzner M, Bielawska A, Morse MA, Rüdiger HA, Sindram D, Hannun YA and Clavien PA: Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in meta-static human colon cancer. Cancer Res. 61:1233–1240. 2001.PubMed/NCBI
40	Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ and Jones RJ: Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 83:2038–2044. 1994.PubMed/NCBI
41	Deming PB, Schafer ZT, Tashker JS, Potts MB, Deshmukh M and Kornbluth S: Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release. Mol Cell Biol. 24:10289–10299. 2004. View Article : Google Scholar : PubMed/NCBI
42	Bueno-da-Silva AE, Brumatti G, Russo FO, Green DR and Amarante-Mendes GP: Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity. Cell Death Differ. 10:592–598. 2003. View Article : Google Scholar : PubMed/NCBI
43	Altieri DC: Survivin and IAP proteins in cell-death mechanisms. Biochem J. 430:199–205. 2010. View Article : Google Scholar : PubMed/NCBI
44	Kreuger MR, Grootjans S, Biavatti MW, Vandenabeele P and D’Herde K: Sesquiterpene lactones as drugs with multiple targets in cancer treatment: Focus on parthenolide. Anticancer Drugs. 23:883–896. 2012.PubMed/NCBI
45	Saikali M, Ghantous A, Halawi R, Talhouk SN, Saliba NA and Darwiche N: Sesquiterpene lactones isolated from indigenous Middle Eastern plants inhibit tumor promoter-induced transformation of JB6 cells. BMC Complement Altern Med. 12:892012. View Article : Google Scholar : PubMed/NCBI
46	Viennois E, Xiao B, Ayyadurai S, Wang L, Wang PG, Zhang Q, Chen Y and Merlin D: Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer. Lab Invest. 94:950–965. 2014. View Article : Google Scholar : PubMed/NCBI
47	Yeh CT, Huang WC, Rao YK, Ye M, Lee WH, Wang LS, Tzeng DT, Wu CH, Shieh YS, Huang CY, et al: A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. Carcinogenesis. 34:2918–2928. 2013. View Article : Google Scholar : PubMed/NCBI