Li Jianfeng, Koczor Christopher A, Saville Kate M, Hayat Faisal, Beiser Alison, McClellan Steven, Migaud Marie E, Sobol Robert W
Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
Cancers (Basel). 2022 Jul 22;14(15):3572. doi: 10.3390/cancers14153572.
Glioblastoma multiforme (GBM) is an incurable brain cancer with an average survival of approximately 15 months. Temozolomide (TMZ) is a DNA alkylating agent for the treatment of GBM. However, at least 50% of the patients treated with TMZ show poor response, primarily due to elevated expression of the repair protein O-methylguanine-DNA methyltransferase (MGMT) or due to defects in the mismatch repair (MMR) pathway. These resistance mechanisms are either somatic or arise in response to treatment, highlighting the need to uncover treatments to overcome resistance. We found that administration of the NAD precursor dihydronicotinamide riboside (NRH) to raise cellular NAD levels combined with PARG inhibition (PARGi) triggers hyperaccumulation of poly(ADP-ribose) (PAR), resulting from both DNA damage-induced and replication-stress-induced PARP1 activation. Here, we show that the NRH/PARGi combination enhances the cytotoxicity of TMZ. Specifically, NRH rapidly increases NAD levels in both TMZ-sensitive and TMZ-resistant GBM-derived cells and enhances the accumulation of PAR following TMZ treatment. Furthermore, NRH promotes hyperaccumulation of PAR in the presence of TMZ and PARGi. This combination strongly suppresses the cell growth of GBM cells depleted of MSH6 or cells expressing MGMT, suggesting that this regimen may improve the efficacy of TMZ to overcome treatment resistance in GBM.
多形性胶质母细胞瘤（GBM）是一种无法治愈的脑癌，平均生存期约为15个月。替莫唑胺（TMZ）是一种用于治疗GBM的DNA烷化剂。然而，至少50%接受TMZ治疗的患者反应不佳，主要是由于修复蛋白O-甲基鸟嘌呤-DNA甲基转移酶（MGMT）表达升高或错配修复（MMR）途径存在缺陷。这些耐药机制要么是体细胞性的，要么是在治疗过程中出现的，这凸显了寻找克服耐药性的治疗方法的必要性。我们发现，给予NAD前体二氢烟酰胺核糖苷（NRH）以提高细胞内NAD水平并联合PARG抑制（PARGi）会触发聚（ADP-核糖）（PAR）的过度积累，这是由DNA损伤诱导和复制应激诱导的PARP1激活所致。在此，我们表明NRH/PARGi组合增强了TMZ的细胞毒性。具体而言，NRH能迅速提高TMZ敏感和耐药的GBM来源细胞中的NAD水平，并增强TMZ处理后PAR的积累。此外，在存在TMZ和PARGi的情况下，NRH促进PAR的过度积累。这种组合强烈抑制了缺失MSH6的GBM细胞或表达MGMT的细胞的生长，表明该方案可能提高TMZ克服GBM治疗耐药性的疗效。
