Most nucleoside anticancer drugs show a primary resistance to p53-deficient or p53-mutated cancer cells and are limited in the clinic to the treatment of hematological malignancies. However, 2′-fluoro-4′-seleno-ara-C (F–Se-Ara-C), a new generation of cytarabine (Ara-C) analogs, exhibited potent antitumor activity against the p53-deficient prostate cancer cell line PC-3. The distinct activity of F–Se-Ara-C was achieved by targeting the synthetic lethal interaction between p53 and mitogen-activated protein kinase-activated protein kinase-2 (MK2). MK2 is a checkpoint effector for DNA damage responses to drive cell cycle arrest and DNA repair in p53-deficient cancer cells. Therefore, targeting MK2 may be an effective therapeutic strategy that induces apoptosis for cancers deficient in p53. F–Se-Ara-C effectively induced anti-prostate cancer activity in vitro and in vivo by inhibition of MK2 activation in p53-deficient prostate cancer cells. Moreover, combining F–Se-Ara-C with cabozantinib, an anticancer drug currently in clinical use, induced synergistic antitumor activity in p53-deficient prostate cancer cells. Taken together, these data show that F–Se-Ara-C may become great anticancer drug candidate with its unique mechanism of action for overcoming the apoptotic resistance of p53-deficient cells by targeting the synthetic lethal interaction.

大多数核苷抗癌药物对p53缺陷或p53突变的癌细胞显示出主要耐药性，并且在临床上仅限于血液系统恶性肿瘤的治疗。然而，新一代阿糖胞苷（Ara-C）类似物2'-fluoro-4'-硒-ara-C（F–Se-Ara-C）对p53缺陷型前列腺癌细胞系表现出有效的抗肿瘤活性。 PC-3。F-Se-Ara-C的独特活性是通过靶向p53和丝裂原活化的蛋白激酶活化的蛋白激酶2（MK2）之间的合成致死相互作用而实现的。MK2是DNA损伤反应的检查点效应物，可驱动p53缺陷癌细胞中的细胞周期停滞和DNA修复。因此，靶向MK2可能是一种有效的治疗策略，可诱导缺乏p53的癌症发生凋亡。F–Se-Ara-C有效诱导抗前列腺癌活性在体内和体外通过抑制p53缺陷型前列腺癌细胞中MK2的活化来实现。此外，将F-Se-Ara-C与目前在临床上使用的抗癌药Cabozantinib结合，可在p53缺陷型前列腺癌细胞中诱导协同抗肿瘤活性。综上所述，这些数据表明，F-Se-Ara-C具有独特的作用机制，可以通过靶向合成致死性相互作用克服p53缺陷细胞的凋亡抗性，从而成为抗癌药物的候选者。