Leukemic cells from different patients exhibit different sensitivity to anticancer drugs including doxorubicin (DOX). Resistance to chemotherapy decreases efficacy of the treatment and promotes cancer recurrence and metastases. One of the approaches to overcome drug resistance includes E2F1-mediated regulation of the р73 protein that belongs to the р53 family. Its ΔNp73 isoform exhibits pro-oncogenic effects, and TAp73 – anti-oncogenic effects. Human cytomegalovirus (HCMV), often found in tumors, suppresses pro-apoptotic pathways and E2F1/p73 in particular. The activity of E2F1 and p73 transcription factors is linked to metabolism of biogenic polyamines. Therefore, it could be suggested that compounds that target polyamine-metabolizing enzymes can sensitize HCMV-infected hematological malignancies to doxorubicin.

Here we report that HCMV infection of ТНР-1 monocytic leukemic cells considerably elevates E2F1 levels and shifts the balance between the р73 isoforms towards ΔNp73 leading to survival of DOX-treated leukemic cells. In contrast, MDL72.527, an inhibitor of polyamine catabolism, decreases ΔNp73/ТАр73 ratio and thus restores sensitivity of the cells to DOX. Our findings indicate the combination of doxorubicin and MDL72.527 may present a novel strategy for therapy of leukemia in patients with and without HCMV infection.

来自不同患者的白血病细胞对包括阿霉素（DOX）在内的抗癌药物表现出不同的敏感性。对化学疗法的抗性降低了治疗的效力并促进了癌症的复发和转移。克服耐药性的方法之一包括E2F1介导的对р53家族的р73蛋白的调控。它的ΔNp73亚型具有促癌作用，而TAp73具有抗癌作用。通常在肿瘤中发现的人类巨细胞病毒（HCMV）会抑制促凋亡途径，尤其是抑制E2F1 / p73。E2F1和p73转录因子的活性与生物多胺的代谢有关。因此，可能提示靶向多胺代谢酶的化合物可以使HCMV感染的血液恶性肿瘤对阿霉素敏感。

在这里，我们报道ТНР-1单核细胞白血病细胞的HCMV感染大大提高了E2F1水平，并使р73亚型之间的平衡向ΔNp73转移，从而导致DOX处理的白血病细胞得以存活。相反，多胺分解代谢的抑制剂MDL72.527降低了ΔNp73/ТАр73的比率，从而恢复了细胞对DOX的敏感性。我们的研究结果表明，阿霉素和MDL72.527的组合可能为患有和不患有HCMV感染的患者提供了一种治疗白血病的新策略。