背景:胶质母细胞瘤(GBM)是最强大的颅内恶性肿瘤。对天然化合物在GBM治疗中的潜在应用的系统探索已成为关键和富有成效的研究途径。
目的:在本研究中,对一组96种二萜化合物作为潜在抗肿瘤药物的储存库进行了系统评估.主要目的是辨别它们在克服替莫唑胺(TMZ)抗性方面的效力。通过广泛的筛选过程,honatisine,七环二萜生物碱,成为最有力的候选人。值得注意的是,honatisine在患者来源的原发性和复发性GBM菌株中具有显着的疗效。随后,我们对这个大院进行了全面的审查,包括GBM培养的球体,GBM类器官(GBO),TMZ抗性GBM细胞系,和GBM细胞的原位异种移植小鼠模型。
结果:我们的调查工作深入研究了honatisine影响的机制基础。可以看出,honatisine促使线粒体蛋白失衡,并引起线粒体未折叠蛋白反应(UPRmt)。这种效应是通过线粒体DNA(mtDNA)编码的亚基的选择性消耗介导的,特别强调线粒体转录因子A(TFAM)的减少。最终的结果是有害的线粒体功能障碍的煽动,最终导致细胞凋亡。分子对接和表面等离子体共振(SPR)实验验证了honatisine对其HMG-boxB结构域内TFAM的结合亲和力。这种结合可能会促进TFAM的磷酸化,并阻碍与重链启动子1(HSP1)结合的TFAM的相互作用,从而增强Lon介导的TFAM降解。最后,体内实验证实了honatisine的抗神经胶质瘤特性。我们全面的毒理学评估强调了其轻度毒性,强调了彻底评估honatisine作为一种新型抗神经胶质瘤药物的必要性。
结论:总之,我们的数据为honatisine选择性诱导细胞凋亡的治疗机制及其克服GBM化疗耐药的能力提供了新的见解。这些作用是通过线粒体蛋白质停滞和功能的破坏来介导的,通过抑制TFAM介导的mtDNA转录来实现。这项研究强调了honatisine作为胶质母细胞瘤治疗有前途的药物的潜力,强调需要进一步探索和调查。
BACKGROUND: Glioblastoma (GBM) represents as the most formidable intracranial malignancy. The systematic exploration of natural compounds for their potential applications in GBM therapy has emerged as a pivotal and fruitful avenue of research.
OBJECTIVE: In the present study, a panel of 96 diterpenoids was systematically evaluated as a repository of potential antitumour agents. The primary objective was to discern their potency in overcoming resistance to temozolomide (TMZ). Through an extensive screening process, honatisine, a heptacyclic diterpenoid alkaloid, emerged as the most robust candidate. Notably, honatisine exhibited remarkable efficacy in patient-derived primary and recurrent GBM strains. Subsequently, we subjected this compound to comprehensive scrutiny, encompassing GBM cultured spheres, GBM organoids (GBOs), TMZ-resistant GBM cell lines, and orthotopic xenograft mouse models of GBM cells.
RESULTS: Our investigative efforts delved into the mechanistic underpinnings of honatisine\'s impact. It was discerned that honatisine prompted mitonuclear protein imbalance and elicited the mitochondrial unfolded protein response (UPRmt). This effect was mediated through the selective depletion of mitochondrial DNA (mtDNA)-encoded subunits, with a particular emphasis on the diminution of mitochondrial transcription factor A (
TFAM). The ultimate outcome was the instigation of deleterious mitochondrial dysfunction, culminating in apoptosis. Molecular docking and surface plasmon resonance (SPR) experiments validated honatisine\'s binding affinity to
TFAM within its HMG-box B domain. This binding may promote phosphorylation of
TFAM and obstruct the interaction of
TFAM bound to heavy strand promoter 1 (HSP1), thereby enhancing Lon-mediated
TFAM degradation. Finally, in vivo experiments confirmed honatisine\'s antiglioma properties. Our comprehensive toxicological assessments underscored its mild toxicity profile, emphasizing the necessity for a thorough evaluation of honatisine as a novel antiglioma agent.
CONCLUSIONS: In summary, our data provide new insights into the therapeutic mechanisms underlying honatisine\'s selective inducetion of apoptosis and its ability to overcome chemotherapy resistance in GBM. These actions are mediated through the disruption of mitochondrial proteostasis and function, achieved by the inhibition of
TFAM-mediated mtDNA transcription. This study highlights honatisine\'s potential as a promising agent for glioblastoma therapy, underscoring the need for further exploration and investigation.