Sartori Andrea, Corno Cristina, De Cesare Michelandrea, Scanziani Eugenio, Minoli Lucia, Battistini Lucia, Zanardi Franca, Perego Paola
Food and Drug Department, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy.
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
Cancers (Basel). 2019 Apr 13;11(4):531. doi: 10.3390/cancers11040531.
Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αβ covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αβ at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.
卵巢癌是最致命的妇科癌症，其特点是诊断较晚，耐药性限制了铂类疗法的疗效。由于某些整合素在包括卵巢癌在内的癌症中上调，它们成为药物递送的潜在靶点。受体酪氨酸激酶在癌症中也失调，其表达与耐药性有关。在此，研究了三种缀合物的抗肿瘤作用，这些缀合物具有与酪氨酸激酶抑制剂舒尼替尼共价连接的整合素αβ细胞外部分的选择性结合剂，作用于不同水平表达酪氨酸激酶VEGFR2和αβ的顺铂敏感和耐药卵巢癌细胞。我们发现三种化合物中的一种在微摩尔范围内能有效抑制药物敏感和耐药细胞的生长，与舒尼替尼相比，耐药细胞中的效力略有增加。同一化合物显著损害细胞迁移和侵袭能力，并减少桩蛋白磷酸化。对裸鼠体内移植的IGROV-1/Pt1细胞进行的抗肿瘤活性研究表明，该缀合物相对于舒尼替尼具有显著活性。综上所述，我们的结果支持整合素靶向的舒尼替尼缀合物在治疗耐药肿瘤方面的应用价值。
