title: CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation.
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.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Zhenghuan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Hong Hua
authors.initials: HH
authors.lastname: Yan
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Marufa
authors.initials: M
authors.lastname: Rumman
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Chodang Pharmaceutical Research Institute, Seoul 152-860, Republic of Korea.
authors.forename: Ki Woon
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Chodang Pharmaceutical Research Institute, Seoul 152-860, Republic of Korea.
authors.forename: Hye-Dong
authors.initials: HD
authors.lastname: Yoo
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007783:Lactones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D031567:Liriodendron / Q000737:chemistry*; D051379:Mice; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D017354:Point Mutation; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D010936:Plant Extracts; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl