Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ.
Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ.
复制标题
DOI：
10.1158/1535-7163.mct-17-0267
复制
发表时间：
2017-09
影响因子：
5.7
通讯作者：
Reyland ME
中科院分区：
文献类型：
--
作者：
Wie SM;Wellberg E;Karam SD;Reyland ME
在接受放射治疗的患者中，非肿瘤组织的损伤可能会导致虚弱，有时甚至是永久性的副作用。我们将蛋白激酶C-增量(PKC-δ)定义为DNA损伤诱导的细胞凋亡的调节因子，并证明了c-Abl和c-δ的磷酸化激活了其促凋亡功能。在这里，我们探索了使用c-src和c-abl的酪氨酸激酶抑制剂(TKI)来阻断PKCδ的激活，从而达到唾液腺的辐射防护。体外实验中，达沙替尼、伊马替尼和博苏替尼均可抑制蛋白激酶Cδ的酪氨酸磷酸化，并抑制IR诱导的细胞凋亡。为了确定TKI是否可以在体内对唾液腺功能提供辐射防护，小鼠接受了TKI和单次或分次剂量的照射。在单次或分次照射后3小时内给予达沙替尼或伊马替尼，60天后唾液腺功能得到75%的保护。持续服用达沙替尼将保护延长到至少5个月，并与唾液腺腺泡细胞再生的组织学证据相关。TKI预处理对HNSCC细胞的克隆存活没有影响，在携带HNSCC细胞来源的异种移植的小鼠中，达沙替尼或伊马替尼与分次照射联合使用并不能促进肿瘤的生长。我们的研究表明，TKIs可能在临床上对接受放射治疗的HNC患者的非肿瘤组织起到保护作用，而不会对癌症治疗产生负面影响。
In patients undergoing irradiation therapy, injury to non-tumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined Protein Kinase C-delta (PKCδ) as a regulator of DNA damage induced apoptosis and have shown that phosphorylation of PKCδ by c-Abl and c-Src activates its pro-apoptotic function. Here we have explored the use of tyrosine kinase inhibitors (TKIs) of c-Src and c-Abl to block activation of PKCδ for radioprotection of the salivary gland. Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCδ and inhibited IR-induced apoptosis in vitro. To determine if TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation. Delivery of dasatinib or imatinib within 3 hours of a single or fractionated dose of irradiation resulted in >75% protection of salivary gland function at 60 days. Continuous dosing with dasatinib extended protection to at least 5 months and correlated with histological evidence of salivary gland acinar cell regeneration. Pretreatment with TKIs had no impact on clonogenic survival of HNSCC cells, and in mice harboring HNSCC cell derived xenografts, combining dasatinib or imatinib with fractionated irradiation did not enhance tumor growth. Our studies indicate that TKIs may be useful clinically to protect non-tumor tissue in HNC patients undergoing radiation therapy, without negatively impacting cancer treatment.