Rizzo Siân, Varache Mathieu, Sayers Edward J, Jones Arwyn T, Tonks Alex, Thomas David W, Ferguson Elaine L
Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
Int J Nanomedicine. 2024 Jun 7;19:5419-5437. doi: 10.2147/IJN.S449185. eCollection 2024.
Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different 'subtypes' in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin's anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin-colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin's cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic.
Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization.
Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote antimicrobial resistance (AMR) and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation.
急性髓系白血病（AML）因其分子格局、表观遗传学和细胞信号改变的异质性而难以治疗。精准医学是AML治疗的一个主要目标，旨在开发可与当前化疗联合用于治疗不同“亚型”患者的药物。我们之前开发了糊精 - 黏菌素缀合物，以应对多重耐药细菌感染的增加并克服剂量限制性肾毒性。最近有证据表明，黏菌素通过抑制细胞内赖氨酸特异性组蛋白去甲基化酶1（LSD1/KDM1A）介导的抗癌活性，这表明糊精 - 黏菌素缀合物可用于治疗癌细胞，包括AML。本研究旨在评估糊精缀合（可降低体内毒性并延长血浆半衰期）是否能增强黏菌素对髓系白血病细胞系的细胞毒性作用，并比较游离抗生素和缀合抗生素的细胞内摄取和定位。
我们的结果确定了一种缀合物（含有8000 g/mol糊精且琥珀酰化程度为1 mol%），与游离黏菌素相比，它在髓系白血病细胞中引起的毒性显著增加。糊精缀合改变了黏菌素引起细胞死亡的机制，从坏死转变为半胱天冬酶3/7依赖性凋亡。相比之下，通过可逆酯连接子而非酰胺进行缀合，对黏菌素诱导的细胞死亡机制没有影响。对荧光标记化合物进行的活细胞共聚焦显微镜观察表明，游离和糊精缀合的黏菌素均被内吞并共定位于溶酶体中，并且增加糊精琥珀酰化的修饰程度会显著降低黏菌素的内化。
虽然由于存在促进抗菌药物耐药性（AMR）的可能性以及抗癌活性所需的相对较高的黏菌素浓度，糊精 - 黏菌素缀合物不太可能用于AML的临床治疗，但通过聚合物缀合增强抗癌药物的有效性，同时减少副作用并改善药物的生物分布，这种能力非常有吸引力，并且这种方法值得进一步研究。
