Abstract：
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics and subsequently inducing apoptosis and RET downregulation. Similar effects were induced by MKT-077, a water-soluble rhodocyanine dye analog known to inhibit mortalin, but with notable toxicity in animals. These observations led us to evaluate recently developed MKT-077 analogs that exhibited higher selectivity to HSP70 proteins and improved bioavailability. We validated the MTC cell-suppressive effects of mortalin depletion in three-dimensional cultures of the human MTC lines, TT, and MZ-CRC-1, and then evaluated different MKT-077 analogs in two- and three-dimensional cell cultures, to show that the MKT-077 analogs, JG-98 and JG-194, effectively and consistently inhibited propagation of TT and MZ-CRC-1 cells in these cultures. Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC.
摘要：
甲状腺髓样癌（MTC）是一种主要由RET原癌基因突变引起的神经内分泌肿瘤。我们之前证明了线粒体分子伴侣的消耗，mortalin,可以有效抑制培养和小鼠异种移植物中的人MTC细胞，通过破坏线粒体生物能学并随后诱导细胞凋亡和RET下调。MKT-077诱导了类似的效果，MKT-077是一种已知抑制mortalin的水溶性Rhodyanine染料类似物，但对动物有明显的毒性。这些观察结果引导我们评估最近开发的MKT-077类似物,其表现出对HSP70蛋白的更高选择性和改善的生物利用度。我们验证了人类MTC细胞系三维培养中mortalin耗竭的MTC细胞抑制作用，TT,和MZ-CRC-1，然后在二维和三维细胞培养中评估不同的MKT-077类似物，为了证明MKT-077类似物，JG-98和JG-194有效且一致地抑制TT和MZ-CRC-1细胞在这些培养物中的增殖。值得注意的是，这些化合物还有效抑制了对vandetanib和cabozantinib耐药的TT和MZ-CRC-1后代的活力.此外，JG-231，一种具有改善的微粒体稳定性的类似物，一致地抑制小鼠的TT和MZ-CRC-1异种移植物。这些数据表明，mortalin抑制可能具有MTC的治疗潜力。
