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Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang, Y.

Blood, 07/31/2003, Vol.102(10), pp.3743-3752 [Tạp chí có phản biện]

ISSN: 0006-4971 ; E-ISSN: 1528-0020 ; DOI: http://dx.doi.org/10.1182/blood-2003-01-0108

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  • Nhan đề:
    Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog
  • Tác giả: Zhang, Y.
  • Chủ đề: Medicine ; Biology ; Chemistry ; Anatomy & Physiology
  • Là 1 phần của: Blood, 07/31/2003, Vol.102(10), pp.3743-3752
  • Mô tả: Acute myelogenous leukemia (AML) is a heterogeneous disease consisting of a variety of different leukemic subtypes. While acute promyelocytic leukemia displays marked sensitivity to the differentiating effects of trans-retinoic acid (tRA), other subtypes of AML display resistance. We now describe a novel compound (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) that induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1, and HL-60R, and in tRA-resistant patient leukemic blasts. The 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations that inhibit committed human bone marrow stem cell proliferation, that is, granulocyte/macrophage colony-forming units (CFU-GMs) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly(adenosine diphosphate) (poly(ADP)) ribose polymerase. While activation of the extracellular signal-regulated kinase (ERK) and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires c-Jun N-terminal kinase (JNK) activation. The 3-Cl-AHPC-mediated cleavage of the antiapoptotic B-cell leukemia XL (Bcl-XL) protein to a proapoptotic 18-kDa product is found in both the M07e cell line and patient leukemic blasts. The 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. While 3-Cl-AHPC does not activate retinoic nuclear receptors, it is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease.
  • Ngôn ngữ: English
  • Số nhận dạng: ISSN: 0006-4971 ; E-ISSN: 1528-0020 ; DOI: http://dx.doi.org/10.1182/blood-2003-01-0108

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