锑剂治疗急性早幼粒细胞白血病的作用研究

Arsenic trioxide (As2O3) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL)，it has been demonstrated that As2O3 is able to bound to PML-RARα fusion proteins, which resulted in initiating PML-RARα oncoprotein degradation, promoting APL cells differentiation and clinical remission of APL patients. However, after injection, As2O3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL. In our previous study, we found that arsenic intermediate metabolites MMAIII and DMAIII are unable to induce the APL cell differentiation. In addition, a few researchers have been indicated the formation of its intermediated metabolites in APL patients may causes the side effects of As2O3. In the current study, we focus on the element Antimony（Sb）which is similar to Arsenic （As) in Group 15 elements. In our preliminary experiment, we found that Sb2O3 was unable to methylate to mon- and dimethylated compounds in rat and mice after oral administration of Sb2O3. In addition, we found the Sb2O3 have strong effects on the induction of Nb4 cell differentiation as well as PML-RARα oncoprotein degradation, and these actions are found to be similar to that of As2O3. More interestingly, we further found the organic antimony compound X has potent effects on induction of arsenic-resistance mutant PML proteins degradation. From above observations, we propose that the Sb2O3 may have a beneficial therapeutic effect (e.g. induction of cell differentiation) on APL patients.

砷剂是世界公认的治疗急性早幼粒细胞白血病（APL）的有效药物之一。然而，研究发现三氧化二砷（As2O3）在人体内可迅代谢为一甲基和二甲基亚砷酸等毒性较高的代谢产物，并且这些代谢产物被证明无诱导APL细胞分化作用。并且，这些甲基化代谢产物被认为是砷剂治疗APL患者过程中引起不良反应的主要原因。针对上述科学问题，我们探索了与“砷”同主族元素的“锑”（Sb）进行了研究，结果发现Sb2O3在动物体内不能够发生甲基化反应，并且Sb2O3具有诱导NB4细胞分化以及降解PML-RARα融合蛋白功能。进一步，我们发现锑的衍生X化合物具有较强的降解难治性PML突变体的作用。我们的研究拟打破单一研究As2O3治疗白血病的临床局面，为多途径治疗白血病提供崭新的科学理论依据，提高APL的治疗疗效，降低其毒副作用。

三氧化二砷（As2O3）可通过靶向性降解急性早幼粒细胞白血病（Acute Promyelocytic Leukemia, APL）的肿瘤特异性致病癌蛋白（PML-RARα融合蛋白），进而诱导早幼粒细胞分化和凋亡从而达到治疗目的。然而三氧化二砷主体内活性甲基化代谢产物MMAIII和DMAIII具有较强的细胞毒性，可能引起严重的毒副作用。在元素周期表中，锑元素和砷元素位于同一主族，理论上两者具有相似的化学性质和功能。并且，锑在体内不会发生甲基化代谢。在本课题的研究中，我们发现锑剂和三氧化二砷类似，可以诱导急性早幼粒细胞白血病细胞的分化，并且能够诱导 PML-RARα融合蛋白发生溶性改变，并进一步降解，使 PML 恢复正常功能，形成核小体。在此基础上，我们发现氧化苯锑能对PML的砷剂耐药突变体产生作用，诱导砷剂耐药的PML突变体发生溶性转变。由此可以证明锑剂对于治疗急性早幼粒细胞白血病的广泛性。进一步的，我们发现使用锌指结构被镉或邻菲罗啉置换锌破坏后，锑剂无法再对PML或PML-RARα蛋白产生作用从而改变蛋白的溶解性。这提示锌指结构在锑剂治疗急性早幼粒细胞白血病过程中的重要性。本项目研究成果的重要性在于证明了锑剂在治疗急性早幼粒细胞白血病过程中的作用，为临床上治疗急性早幼粒细胞白血病提供了新的思路和方法。