Suraj Rejitha, Radhamani Suraj, Meehan-Andrews Terri, Bradley Christopher
School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.
Faculty of Science Technology and Engineering, School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences , La Trobe University, P.O. Box 199, Bendigo, VIC, 3550, Australia.
Apoptosis. 2017 Aug;22(8):988-1000. doi: 10.1007/s10495-017-1380-4.
The concept to fight against tumour resistance is to use chemosensitizers that selectively sensitize tumour cells to chemotherapeutic drugs without affecting normal tissue. In this study, the chemosensitizing potential of a novel benzoxazine derivative in combination with Doxorubicin, a DNA damaging chemotherapeutic drug was evaluated. The results of this study showed that the compound LTUR6 is a potent chemosensitizer of Doxorubicin in colon cancer cell lines, HCT116 and HT29. It was also observed that LTUR6 delayed the resolution of Doxorubicin-induced γH2AX, a specific marker of unrepaired DNA DSB, and prolonged cell cycle arrest in both cell lines. This eventually led to DNA fragmentation, caspase activation and ultimately apoptosis in LTUR6 treated cell lines. Results of western blot analysis revealed that LTUR6 significantly inhibited the phosphorylation of DSB repair enzyme AKT, in response to Doxorubicin-induced DSB. We propose that the chemosensitization observed following inhibition of PI3K is likely due to the involvement of a number of downstream targets of AKT.
对抗肿瘤耐药性的概念是使用化学增敏剂，这些增敏剂能选择性地使肿瘤细胞对化疗药物敏感，而不影响正常组织。在本研究中，评估了一种新型苯并恶嗪衍生物与阿霉素（一种DNA损伤化疗药物）联合使用时的化学增敏潜力。本研究结果表明，化合物LTUR6是阿霉素在结肠癌细胞系HCT116和HT29中的一种有效化学增敏剂。还观察到，LTUR6延迟了阿霉素诱导的γH2AX（未修复DNA双链断裂的特异性标志物）的消退，并延长了这两种细胞系中的细胞周期停滞。这最终导致了LTUR6处理的细胞系中的DNA片段化、半胱天冬酶激活并最终引发凋亡。蛋白质印迹分析结果显示，LTUR6显著抑制了DSB修复酶AKT的磷酸化，以应对阿霉素诱导的DSB。我们认为，抑制PI3K后观察到的化学增敏作用可能是由于AKT的许多下游靶点的参与。
