Rossello Armando, Nuti Elisa, Ferrini Silvano, Fabbi Marina
IRCCS AOU San Martino- IST, Department of Integrated Oncological Therapies, Genoa, Italy.
Curr Drug Targets. 2016;17(16):1908-1927. doi: 10.2174/1389450117666160727143618.
A disintegrin and metalloprotease (ADAM)17 is a sheddase, capable of releasing the ectodomains of membrane proteins such as growth factors (e.g. Epidermal Growth Factor Receptor ligands), cytokines and their receptors, adhesion and signaling molecules. These activities regulate several physiological and pathological processes including inflammation, tumor growth and metastatic progression. In this review, we will summarize ADAM17 biology and focus on its role in cancer and the possible usage of ADAM17 inhibitors in cancer therapy. Recent achievements in this area include the development of small molecule metalloprotease inhibitors with enhanced specificity for ADAM17, monoclonal antibodies, and synthetic short RNA molecules for gene silencing. These approaches successfully inhibited cancer cell growth and invasiveness or sensitized them to cytotoxic drugs, ionizing radiations or targeted therapies, in preclinical studies. These findings suggest the repositioning of ADAM17 inhibitors, which have yet proven unsuccessful as anti-inflammatory agents, for the development of new anti-cancer therapies, particularly in EGFR ligand-dependent cancers. Future studies should address ADAM17 inhibitors as short-term treatments in combination with different anti-cancer therapies.
解整合素金属蛋白酶17（ADAM17）是一种脱落酶，能够释放膜蛋白的胞外结构域，如生长因子（如表皮生长因子受体配体）、细胞因子及其受体、黏附分子和信号分子。这些活性调节多种生理和病理过程，包括炎症、肿瘤生长和转移进展。在本综述中，我们将总结ADAM17的生物学特性，并重点关注其在癌症中的作用以及ADAM17抑制剂在癌症治疗中的可能用途。该领域的最新成果包括开发对ADAM17具有更高特异性的小分子金属蛋白酶抑制剂、单克隆抗体以及用于基因沉默的合成短RNA分子。在临床前研究中，这些方法成功抑制了癌细胞的生长和侵袭性，或使它们对细胞毒性药物、电离辐射或靶向治疗敏感。这些发现表明，尚未证明作为抗炎药成功的ADAM17抑制剂可重新用于开发新的抗癌疗法，特别是在表皮生长因子受体（EGFR）配体依赖性癌症中。未来的研究应探讨将ADAM17抑制剂作为短期治疗与不同抗癌疗法联合使用的情况。
