Department of Orthopaedics, University Hospital Heidelberg, 69118 Heidelberg, Germany.
Cells. 2023 Dec 27;13(1):61. doi: 10.3390/cells13010061.
Although urgently needed, no significant improvements in osteosarcoma (OS) therapy have been achieved within the last decades. Here, we present a new therapeutic approach based on drug combinations consisting of mitochondrial complex I (MCI) inhibitors and ionophores that induce cancer cell-specific cell death based on a modulation of cellular energy metabolism and intracellular pH (pHi) named the Warburg Trap (WT). The effects of several drug combinations on intracellular pH, cell viability, colony-forming capacity and expression of WNT-target genes were analysed using OS cell lines and primary human osteoblasts (HOB). Tumour take rates and tumour volumes were analysed in vivo using a chicken chorioallantoic membrane assay (CAM). Several WT drug combinations induced the intracellular acidification and apoptotic cell death in OS cells, whereas HOBs tolerated the treatment. A significant inhibition of the colony-forming ability of OS cells and downregulation of WNT-target genes suggest that cancer stem cells (CSCs) are also targeted by the WT approach. In vivo, we observed a significant reduction in the tumour take rates in response to WT drug treatment. Our data suggest that the Warburg Trap is a promising approach for the development of a novel and effective OS therapy to replace or supplement the current OS chemotherapy.
尽管急需，但在过去几十年中，骨肉瘤（OS）治疗并未取得显著进展。在这里，我们提出了一种新的治疗方法，该方法基于药物组合，这些药物组合由线粒体复合物 I（MCI）抑制剂和离子载体组成，基于对细胞能量代谢和细胞内 pH（pHi）的调节来诱导癌细胞特异性细胞死亡，这种方法称为沃伯格陷阱（WT）。使用 OS 细胞系和原代人成骨细胞（HOB）分析了几种药物组合对细胞内 pH、细胞活力、集落形成能力和 WNT 靶基因表达的影响。使用鸡绒毛尿囊膜分析（CAM）在体内分析肿瘤接种率和肿瘤体积。几种 WT 药物组合诱导 OS 细胞内酸化和凋亡性细胞死亡，而 HOB 耐受该治疗。OS 细胞集落形成能力的显著抑制和 WNT 靶基因的下调表明，癌症干细胞（CSCs）也被 WT 方法靶向。在体内，我们观察到对 WT 药物治疗的肿瘤接种率显着降低。我们的数据表明，沃伯格陷阱是开发新型有效骨肉瘤治疗方法的有前途的方法，可以替代或补充当前的骨肉瘤化疗。
