Lobba Aline R M, Alvarez-Flores Miryam Paola, Fessel Melissa Regina, Buri Marcus Vinicius, Oliveira Douglas S, Gomes Renata N, Cunegundes Priscila S, DeOcesano-Pereira Carlos, Cinel Victor D, Chudzinski-Tavassi Ana M
Centre of Excellence in New Target Discovery-CENTD, Butantan Institute, São Paulo, Brazil.
Development and Innovation Centre, Butantan Institute, Butantan Institute, São Paulo, Brazil.
Front Mol Biosci. 2022 Aug 16;9:936107. doi: 10.3389/fmolb.2022.936107. eCollection 2022.
Salivary glands are vital structures responsible for successful tick feeding. The saliva of ticks contains numerous active molecules that participate in several physiological processes. A Kunitz-type factor Xa (FXa) inhibitor, similar to the tissue factor pathway inhibitor (TFPI) precursor, was identified in the salivary gland transcriptome of ticks. The recombinant mature form of this Kunitz-type inhibitor, named Amblyomin-X, displayed anticoagulant, antiangiogenic, and antitumor properties. Amblyomin-X is a protein that inhibits FXa in the blood coagulation cascade and acts via non-hemostatic mechanisms, such as proteasome inhibition. Amblyomin-X selectively induces apoptosis in cancer cells and promotes tumor regression through these mechanisms. Notably, the cytotoxicity of Amblyomin-X seems to be restricted to tumor cells and does not affect non-tumorigenic cells, tissues, and organs, making this recombinant protein an attractive molecule for anticancer therapy. The cytotoxic activity of Amblyomin-X on tumor cells has led to vast exploration into this protein. Here, we summarize the function, action mechanisms, structural features, pharmacokinetics, and biodistribution of this tick Kunitz-type inhibitor recombinant protein as a promising novel antitumor drug candidate.
唾液腺是蜱成功取食所必需的重要结构。蜱的唾液含有许多参与多种生理过程的活性分子。在蜱的唾液腺转录组中鉴定出一种类似于组织因子途径抑制剂（TFPI）前体的Kunitz型因子Xa（FXa）抑制剂。这种Kunitz型抑制剂的重组成熟形式名为Amblyomin-X，具有抗凝、抗血管生成和抗肿瘤特性。Amblyomin-X是一种在血液凝固级联反应中抑制FXa的蛋白质，它通过蛋白酶体抑制等非止血机制发挥作用。Amblyomin-X通过这些机制选择性地诱导癌细胞凋亡并促进肿瘤消退。值得注意的是，Amblyomin-X的细胞毒性似乎仅限于肿瘤细胞，不会影响非致瘤细胞、组织和器官，这使得这种重组蛋白成为一种有吸引力的抗癌治疗分子。Amblyomin-X对肿瘤细胞的细胞毒性促使人们对这种蛋白质进行了大量研究。在此，我们总结了这种蜱Kunitz型抑制剂重组蛋白作为一种有前景的新型抗肿瘤药物候选物的功能、作用机制、结构特征、药代动力学和生物分布。
