Kuo Ching-Ying, Chou Wen-Cheng, Wu Chin-Chung, Wong Teng-Song, Kakadiya Rajesh, Lee Te-Chang, Su Tsann-Long, Wang Hui-Chun
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Oncotarget. 2015 Sep 22;6(28):25770-83. doi: 10.18632/oncotarget.4514.
Alkylating agents are frequently used as first-line chemotherapeutics for various newly diagnosed cancers. Disruption of genome integrity by such agents can lead to cell lethality if DNA lesions are not removed. Several DNA repair mechanisms participate in the recovery of mono- or bi-functional DNA alkylation. Thus, DNA repair capacity is correlated with the therapeutic response. Here, we assessed the function of novel water-soluble N-mustard BO-1055 (ureidomustin) in DNA damage response and repair mechanisms. As expected, BO-1055 induces ATM and ATR-mediated DNA damage response cascades, including downstream Chk1/Chk2 phosphorylation, S/G2 cell-cycle arrest, and cell death. Further investigation revealed that cell survival sensitivity to BO-1055 is comparable to that of mitomycin C. Both compounds require nucleotide excision repair and homologous recombination, but not non-homologous end-joining, to repair conventional cross-linking DNA damage. Interestingly and unlike mitomycin C and melphalan, MGMT activity was also observed in BO-1055 damage repair systems, which reflects the occurrence of O-alkyl DNA lesions. Combined treatment with ATM/ATR kinase inhibitors significantly increases BO-1055 sensitivity. Our study pinpoints that BO-1055 can be used for treating tumors that with deficient NER, HR, and MGMT DNA repair genes, or for synergistic therapy in tumors that DNA damage response have been suppressed.
烷化剂经常被用作各种新诊断癌症的一线化疗药物。如果DNA损伤未被修复，这类药物对基因组完整性的破坏会导致细胞死亡。几种DNA修复机制参与单功能或双功能DNA烷基化的修复。因此，DNA修复能力与治疗反应相关。在此，我们评估了新型水溶性N-芥子气BO-1055（脲氮芥）在DNA损伤反应和修复机制中的作用。正如预期的那样，BO-1055诱导ATM和ATR介导的DNA损伤反应级联，包括下游Chk1/Chk2磷酸化、S/G2期细胞周期阻滞和细胞死亡。进一步研究表明，细胞对BO-1055的存活敏感性与丝裂霉素C相当。两种化合物都需要核苷酸切除修复和同源重组来修复传统的交联DNA损伤，而非同源末端连接则不需要。有趣的是，与丝裂霉素C和美法仑不同，在BO-1055损伤修复系统中也观察到了MGMT活性，这反映了O-烷基DNA损伤的发生。联合使用ATM/ATR激酶抑制剂可显著提高对BO-1055的敏感性。我们的研究指出，BO-1055可用于治疗NER、HR和MGMT DNA修复基因缺陷的肿瘤，或用于对DNA损伤反应已被抑制的肿瘤进行协同治疗。
