Dimitrios Diamantis, Antonios D Tsiailanis, Christina Papaemmanouil, Maria-Christina Nika, Zoi Kanaki, Simona Golic Grdadolnik, Andrej Babic, Eleftherios Paraskevas Tzakos, Isabelle Fournier, Michel Salzet, Prem Prakash Kushwaha, Nikolaos S Thomaidis, Theodoros Rampias, Eswar Shankar, Serdar Karakurt, Sanjay Gupta, Andreas G Tzakos
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引用次数: 0
Abstract
Elevated levels of alkaline phosphatase (ALP) in the tumor microenvironment (TME) are a hallmark of cancer progression and thus inhibition of ALP could serve as an effective approach against cancer. Herein, we developed a novel prodrug approach to tackle cancer that bears self-inhibiting alkaline phosphatase-responsiveness properties that can enhance at the same time the solubility of the parent compound. To probe this novel concept, we selected apigenin as the cytotoxic agent since we first unveiled, that it directly interacts and inhibits ALP activity. Consequently, we rationally designed and synthesized, using a self-immolative linker, an ALP responsive apigenin-based phosphate prodrug, phospho-apigenin. Phospho-apigenin markedly increased the stability of the parent compound apigenin. Furthermore, the prodrug exhibited enhanced antiproliferative effect in malignant cells with elevated ALP levels, compared to apigenin. This recorded potency of the developed prodrug was further confirmed in vivo where phospho-apigenin significantly suppressed by 52.8% the growth of PC-3 xenograft tumors.Communicated by Ramaswamy H. Sarma.
肿瘤微环境(TME)中碱性磷酸酶(ALP)水平的升高是癌症进展的标志,因此抑制 ALP 可作为一种有效的抗癌方法。在此,我们开发了一种新的原药方法来治疗癌症,这种方法具有自我抑制碱性磷酸酶的特性,可以同时提高母体化合物的溶解度。为了探究这个新概念,我们选择了芹菜素作为细胞毒剂,因为我们首次发现芹菜素能直接与碱性磷酸酶相互作用并抑制其活性。因此,我们利用自巯基连接体合理地设计和合成了一种对 ALP 有反应的芹菜素磷酸盐原药--磷酸芹菜素。磷酸化芹菜素显著提高了母体化合物芹菜素的稳定性。此外,与芹菜素相比,该原药在 ALP 水平升高的恶性细胞中表现出更强的抗增殖作用。磷酸芹菜素显著抑制了 PC-3 异种移植肿瘤的生长,抑制率为 52.8%。
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.