Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.
Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.
复制标题
肿瘤细胞代谢的修饰调节对CHK1抑制剂诱导的DNA损伤的敏感性。
DOI：
10.1038/srep40778
复制
发表时间：
2017-01-20
影响因子：
4.6
通讯作者：
Massey AJ
中科院分区：
文献类型：
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作者：
Massey AJ
Chk1激酶抑制剂目前正在临床研究中，作为细胞毒性化疗的增强剂，并与抗代谢物药物联合使用，通过抑制核苷酸或脱氧核糖核苷酸的生物合成来增加复制应激。抑制其他对支持DNA复制所需构建块供应至关重要的代谢途径可能导致DNA损伤增加，并与Chk1抑制剂协同作用。小分子代谢调节剂筛选发现Chk1抑制剂与氯喹或LDHA/LDHB抑制剂GSK 2837808A之间存在组合活性。化合物，如2-脱氧葡萄糖或6-氨基烟碱酰胺，可以减少细胞进行活跃复制的比例，使肿瘤细胞更能抵抗Chk1抑制剂诱导的DNA损伤。停用葡萄糖或谷氨酰胺诱导G1和G2/M阻滞，但不增加DNA损伤，并通过自磷酸化降低Chk1的表达和激活。这表明Chk1激酶的表达和激活与细胞进行活跃的DNA复制有关。谷氨酰胺饥饿使肿瘤细胞对Chk1抑制剂诱导的DNA损伤更具抵抗力，谷氨酰胺饥饿的逆转恢复了肿瘤细胞对Chk1抑制剂诱导的DNA损伤的敏感性。Chk1抑制剂对于肿瘤中含有大量复制细胞的患者可能是一种潜在有用的治疗方法。
Chk1 kinase inhibitors are currently under clinical investigation as potentiators of cytotoxic chemotherapy and demonstrate potent activity in combination with anti-metabolite drugs that increase replication stress through the inhibition of nucleotide or deoxyribonucleotide biosynthesis. Inhibiting other metabolic pathways critical for the supply of building blocks necessary to support DNA replication may lead to increased DNA damage and synergy with an inhibitor of Chk1. A screen of small molecule metabolism modulators identified combinatorial activity between a Chk1 inhibitor and chloroquine or the LDHA/LDHB inhibitor GSK 2837808A. Compounds, such as 2-deoxyglucose or 6-aminonicotinamide, that reduced the fraction of cells undergoing active replication rendered tumour cells more resistant to Chk1 inhibitor-induced DNA damage. Withdrawal of glucose or glutamine induced G1 and G2/M arrest without increasing DNA damage and reduced Chk1 expression and activation through autophosphorylation. This suggests the expression and activation of Chk1 kinase is associated with cells undergoing active DNA replication. Glutamine starvation rendered tumour cells more resistant to Chk1 inhibitor-induced DNA damage and reversal of the glutamine starvation restored the sensitivity of tumour cells to Chk1 inhibitor-induced DNA damage. Chk1 inhibitors may be a potentially useful therapeutic treatment for patients whose tumours contain a high fraction of replicating cells.