Chandra Joya, Hackbarth Jennifer, Le Son, Loegering David, Bone Nancy, Bruzek Laura M, Narayanan Ven L, Adjei Alex A, Kay Neil E, Tefferi Ayalew, Karp Judith E, Sausville Edward A, Kaufmann Scott H
Division of Oncology Research, Guggenheim 1301, Mayo Clinic, 200 First St, SW, Rochester, MN 55901, USA.
Blood. 2003 Dec 15;102(13):4512-9. doi: 10.1182/blood-2003-02-0562. Epub 2003 Aug 14.
Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned.
阿地福司汀（NSC 680410）是酪氨酸磷酸化抑制剂AG957的类似物，先前研究表明，它可诱导慢性粒细胞白血病（CML）细胞系和临床样本中的Bcr/abl下调，随后克隆生存能力丧失。阿地福司汀在体外对CML髓系祖细胞表现出选择性，并且在对甲磺酸伊马替尼耐药的K562细胞中仍具有活性。在本研究中，对阿地福司汀的作用机制进行了更深入的体外研究。初步研究表明，阿地福司汀可诱导多种Bcr/abl阳性细胞凋亡，包括急性髓性白血病（AML）原始细胞和细胞系以及慢性淋巴细胞白血病（CLL）样本。进一步研究表明，阿地福司汀导致细胞内过氧化物生成，随后出现DNA链断裂，在含有野生型p53的细胞中，会引发由p53磷酸化和上调组成的典型DNA损伤反应。重要的是，抗氧化剂N-乙酰半胱氨酸（NAC）可减弱这些事件，而用丁硫氨酸亚砜胺（BSO）消耗谷胱甘肽则会增强这些事件。总的来说，这些结果不仅概述了阿地福司汀损伤髓系和淋巴系白血病细胞的机制，还表明这种新型药物可能具有比最初设想更广泛的活性谱。
