PDF(Pubmed)
Abstract：
The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of medicinal plants for developing anticancer drugs has garnered considerable attention owing to their diverse mechanisms of action. In this study, 100 plant extracts of flora from the Republic of Korea were screened to search for novel agents with anti-DLBCL effects. Among them, Ajania pacifica (Nakai) K. Bremer and Humphries extract (APKH) efficiently suppressed the survival of DLBCL cells, while showing minimal toxicity toward normal murine bone marrow cells. APKH suppressed the expression of anti-apoptotic BCL2 family members, causing an imbalance between the pro-apoptotic and anti-apoptotic BCL2 members. This disrupted mitochondrial membrane potential, cytochrome c release, and pro-caspase-3 activation and eventually led to DLBCL cell death. Importantly, MYC expression was markedly downregulated by APKH and ectopic expression of MYC in DLBCL cells abolished the pro-apoptotic effects of APKH. These results demonstrate that APKH exerts anti-DLBCL effects by inhibiting MYC expression. Moreover, when combined with doxorubicin, an essential component of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), APKH synergistically enhanced the therapeutic effect of doxorubicin. This indicates that APKH may overcome drug resistance, which is common in patients with refractory/relapsed DLBCL. To identify compounds with anti-DLBCL activities in APKH, the chemical profile analysis of APKH was performed using UPLC-QTOF/MSe analysis and assessed for its anticancer activity. Based on the UPLC-QTOF/MSe chemical profiling, it is conceivable that APKH may serve as a novel agent targeting MYC and sensitizing drug-resistant DLBCL cells to CHOP chemotherapy. Further studies to elucidate how the compounds in APKH exert tumor-suppressive role in DLBCL are warranted.
摘要：
在弥漫性大B细胞淋巴瘤（DLBCL）患者中，原癌基因MYC经常失调，并在疾病进展中起关键作用。改善DLBCL患者的临床预后,制定针对MYC的战略至关重要。使用药用植物开发抗癌药物由于其不同的作用机制而引起了相当大的关注。在这项研究中,筛选了100种来自大韩民国的植物提取物，以寻找具有抗DLBCL作用的新型药物。其中,Ajaniapacifica（Nakai）K.Bremer和Humphries提取物（APKH）有效抑制DLBCL细胞的存活，同时对正常小鼠骨髓细胞毒性最小。APKH抑制抗凋亡BCL2家族成员的表达，导致促凋亡和抗凋亡BCL2成员之间的不平衡。这种破坏的线粒体膜电位，细胞色素c释放，和pro-caspase-3激活并最终导致DLBCL细胞死亡。重要的是,MYC表达被APKH显著下调，MYC在DLBCL细胞中的异位表达消除了APKH的促凋亡作用。这些结果证明APKH通过抑制MYC表达发挥抗DLBCL作用。此外，当与阿霉素联合使用时，CHOP方案的重要组成部分(环磷酰胺，阿霉素,长春新碱,和泼尼松)，APKH协同增强阿霉素的治疗效果。这表明APKH可以克服耐药性，这在难治性/复发性DLBCL患者中很常见。为了鉴定APKH中具有抗DLBCL活性的化合物，使用UPLC-QTOF/MSe分析进行APKH的化学谱分析并评估其抗癌活性。基于UPLC-QTOF/MSe化学剖析，可以想象,APKH可能是靶向MYC并使耐药DLBCL细胞对CHOP化疗敏感的新型药物.有必要进一步研究阐明APKH中的化合物如何在DLBCL中发挥肿瘤抑制作用。
