Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo. We found that IIIM-290 induced apoptosis through upregulation of different apoptotic proteins like PUMA, BAX, cytochrome c, cleaved (active) caspase-3, and cleaved PARP in MOLT-4 cells. Moreover, IIIM-290 abated mitochondrial membrane potential, elevated calcium levels, reactive oxygen species, and arrested growth of MOLT-4 cells in the synthesis (S) phase of the cell cycle. Interestingly, the elevation in proapoptotic markers was p53 dependent—the silencing of p53 abrogated apoptosis (programmed cell death) triggered by IIIM-290 in MOLT-4 cells. Furthermore, IIIM-290 significantly enhanced the survival of animals with P388 and L1210 leukemia. Thus, our results put IIIM-290 as a potential candidate for the anticancer lead.

中文翻译：

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rohitukine 衍生物 IIIM-290 在急性淋巴细胞白血病细胞中诱导 p53 依赖性线粒体凋亡

Rohitukine 是一种从Dysoxylum binectariferum 中提取的色酮生物碱，具有有益的抗癌活性。我们之前的研究表明，一种新的 Rohitukine 衍生物 IIIM-290 限制了体内和体外胰腺癌的生长。在目前的研究结果中，我们报告了 IIIM-290 在 MOLT-4 细胞（急性淋巴细胞白血病）中诱导细胞死亡的机制及其在体内对各种鼠白血病肿瘤模型的抗癌潜力. 我们发现 IIIM-290 通过上调 MOLT-4 细胞中不同的凋亡蛋白，如 PUMA、BAX、细胞色素 c、裂解的（活性）caspase-3 和裂解的 PARP 来诱导细胞凋亡。此外，IIIM-290 在细胞周期的合成 (S) 阶段降低线粒体膜电位、升高钙水平、活性氧并阻止 MOLT-4 细胞的生长。有趣的是，促凋亡标记物的升高是 p53 依赖性的——p53 的沉默消除了 MOLT-4 细胞中 IIIM-290 触发的凋亡（程序性细胞死亡）。此外，IIIM-290 显着提高了 P388 和 L1210 白血病动物的存活率。因此，我们的结果将 IIIM-290 作为抗癌先导物的潜在候选物。