Department of Pathology, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; Center for Molecular Discovery, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
Department of Pathology, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; Center for Molecular Discovery, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.
Semin Cancer Biol. 2021 Jan;68:199-208. doi: 10.1016/j.semcancer.2020.02.004. Epub 2020 Feb 7.
While current treatment regimens for acute leukemia can dramatically improve patient survival, there remains room for improvement. Due to its roles in cell differentiation, cell survival, and apoptotic signaling, modulation of the cyclic AMP (cAMP) pathway has provided a meaningful target in hematological malignancies. Several studies have demonstrated that gene expression profiles associated with increased pro-survival cAMP activity or downregulation of various pro-apoptotic factors associated with the cAMP pathway are apparent in acute leukemia patients. Previous work to increase leukemia cell intracellular cAMP focused on the use of cAMP analogs, stimulating cAMP production via transmembrane-associated adenylyl cyclases, or decreasing cAMP degradation by inhibiting phosphodiesterase activity. However, targeting cyclic nucleotide efflux by ATP-binding cassette (ABC) transporters represents an unexplored approach for modulation of intracellular cyclic nucleotide levels. Preliminary studies have shown that inhibition of cAMP efflux can stimulate leukemia cell differentiation, cell growth arrest, and apoptosis, indicating that targeting cAMP efflux may show promise for future therapeutic development. Furthermore, inhibition of cyclic nucleotide transporter activity may also contribute multiple anticancer benefits by reducing extracellular pro-survival signaling in malignant cells. Hence, several opportunities for drug repurposing may exist for targeting cyclic nucleotide transporters.
虽然目前治疗急性白血病的方案可以显著提高患者的生存率，但仍有改进的空间。由于环磷酸腺苷 (cAMP) 途径在细胞分化、细胞存活和凋亡信号转导中的作用，该途径的调节已成为血液恶性肿瘤的一个有意义的靶点。多项研究表明，在急性白血病患者中，与细胞存活相关的 cAMP 活性增加或与 cAMP 途径相关的各种促凋亡因子下调相关的基因表达谱明显。先前增加白血病细胞内 cAMP 的工作集中在使用 cAMP 类似物、通过跨膜相关腺苷酸环化酶刺激 cAMP 产生或通过抑制磷酸二酯酶活性减少 cAMP 降解。然而，通过三磷酸腺苷结合盒 (ABC) 转运体靶向环核苷酸外排代表了调节细胞内环核苷酸水平的一种未被探索的方法。初步研究表明，抑制 cAMP 外排可以刺激白血病细胞分化、细胞生长停滞和凋亡，表明靶向 cAMP 外排可能为未来的治疗开发带来希望。此外，通过减少恶性细胞中外源性促存活信号，抑制环核苷酸转运体活性也可能带来多种抗癌益处。因此，针对环核苷酸转运体可能存在一些药物再利用的机会。
