The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death
The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death
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DOI：
10.1182/blood-2007-05-089219
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Petit, Isabelle;Karajannis, Matthias A.;Rafii, Shahin
白血病细胞与血管细胞的粘附可能使其对化疗药物产生耐药性。我们假设破坏白血病细胞的细胞骨架稳定性和干扰血管细胞的相互作用会促进白血病细胞死亡。我们证明了低剂量和无毒剂量的微管不稳定剂combretastatin-A4phosphate （CA4P）在体外抑制白血病细胞增殖，诱导有丝分裂停止和细胞死亡。用CA4P治疗急性髓系白血病（AMLs）可导致线粒体膜电位破坏、促凋亡线粒体膜蛋白释放和DNA断裂，部分通过caspase依赖的方式导致细胞死亡。此外，CA4P增加细胞内活性氧（ROS），抗氧化处理对细胞死亡提供部分保护，表明ROS积累有助于CA4P诱导的AML细胞毒性。在体内，CA4P抑制白血病细胞的增殖和循环，减少血管周围白血病浸润的程度，延长异种移植小鼠的生存期，而不引起血液毒性。CA4P通过下调粘附分子VCAM-1的表达，从而增加白血病细胞的死亡，从而减少白血病细胞与新血管的相互作用。这些数据表明，CA4P通过线粒体损伤和下调VCAM-1靶向循环和血管粘附的白血病细胞，而不会引起血液毒性。因此，CA4P为治疗难治性器官浸润性白血病提供了有效手段。
Adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents. We hypothesized that disruption of leukemic cell cytoskeletal stability and interference with vascular cell interactions would promote leukemic cell death. We demonstrate that low and nontoxic doses of microtubule-destabilizing agent combretastatin-A4phosphate (CA4P) inhibit leukemic cell proliferation in vitro and induce mitotic arrest and cell death. Treatment of acute myeloid leukemias (AMLs) with CA4P leads to disruption of mitochondrial membrane potential, release of proapoptotic mitochondrial membrane proteins, and DNA fragmentation, resulting in cell death in part through a caspase-dependent manner. Furthermore, CA4P increases intracellular reactive oxygen species (ROS), and antioxidant treatment imparts partial protection from cell death, suggesting that ROS accumulation contributes to CA4P-induced cytotoxicity in AML. In vivo, CA4P inhibited proliferation and circulation of leukemic cells and diminished the extent of perivascular leukemic infiltrates, prolonging survival of mice that underwent xenotransplantation without inducing hematologic toxicity. CA4P decreases the interaction of leukemic cells with neovessels by down-regulating the expression of the adhesion molecule VCAM-1 thereby augmenting leukemic cell death. These data suggest that CA4P targets both circulating and vascularadherent leukemic cells through mitochondrial damage and down-regulation of VCAM-1 without incurring hematologic toxicities. As such, CA4P provides for an effective means to treat refractory organ-infiltrating leukemias.