Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

中文翻译：

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急性髓细胞白血病细胞对二烯酮化合物 VLX1570 的敏感性与泛素-蛋白酶体系统的抑制有关

已广泛报道具有 1,5-diaryl-3-oxo-1,4-pentadienyl 药效团的二烯酮化合物显示出肿瘤细胞选择性。这些化合物靶向泛素-蛋白酶体系统 (UPS)，该系统已知对肿瘤细胞的活力至关重要。还报道了氧化应激的诱导、谷胱甘肽的消耗和高分子量 (HMW) 复合物的诱导。我们在这里检查了急性髓性白血病 (AML) 细胞对二烯酮化合物 VLX1570 的反应。AML 细胞具有相对较高的蛋白质周转率，并且据报道对还原型谷胱甘肽的消耗敏感。我们发现不同细胞遗传学背景的 AML 细胞对 VLX1570 敏感，药物暴露导致泛素复合物积累，诱导 ER 应激，以及以剂量依赖性方式丧失细胞活力。观察到半胱天冬酶活化，但不是细胞活力丧失所必需的。还观察到谷胱甘肽耗尽，但与 VLX1570 敏感性无关。HMW 复合物的形成发生在 VLX1570 的浓度高于细胞活力丧失所需的浓度下，并且没有因谷胱甘肽耗尽而增强。为了研究 VLX1570 的作用，我们开发了斑马鱼 AML 的 PDX 模型并证实了体内的抗生长活性。我们的研究结果表明，VLX1570 在 AML 细胞中诱导 UPS 抑制，并鼓励进一步开发可用于癌症治疗的化合物。HMW 复合物的形成发生在 VLX1570 的浓度高于细胞活力丧失所需的浓度下，并且没有因谷胱甘肽耗尽而增强。为了研究 VLX1570 的作用，我们开发了斑马鱼 AML 的 PDX 模型并证实了体内的抗生长活性。我们的研究结果表明，VLX1570 在 AML 细胞中诱导 UPS 抑制，并鼓励进一步开发可用于癌症治疗的化合物。