Doddapaneni Ravi, Tucker Jason D, Lu Pei J, Lu Qi L
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA.
Int J Mol Sci. 2025 Mar 15;26(6):2661. doi: 10.3390/ijms26062661.
The mortality rate of breast cancer remains high, despite remarkable advances in chemotherapy. Therefore, it is imperative to identify new treatment options. In the present study, we investigated whether the metabolite ribitol enhances the cytotoxic effect of shikonin against breast cancer in vitro. Here, we screened a panel of small molecules targeting energy metabolism against breast cancer. The results of the study revealed that ribitol enhances shikonin's growth-inhibitory effects, with significant synergy. A significant ( < 0.01) increase in the percentage (56%) of apoptotic cells was detected in the combined treatment group, compared to shikonin single-treatment group (38%), respectively. The combined ribitol and shikonin treatment led to significant arrest of cell proliferation (40%) ( < 0.01) compared to untreated cells, as well as the induction of apoptosis. This was associated with upregulation of p53 ( < 0.05) and downregulation of c-Myc ( < 0.01), Bcl-xL ( < 0.001), and Mcl-1 ( < 0.05). Metabolomic analysis supports the premise that inhibition of the Warburg effect is involved in shikonin-induced cell death, which is likely further enhanced by dysregulation of glycolysis and the tricarboxylic acid (TCA) cycle, afflicted by ribitol treatment. In conclusion, the present study demonstrates that the metabolite ribitol selectively enhances the cytotoxic effect mediated by shikonin against breast cancer in vitro.
尽管化疗取得了显著进展，但乳腺癌的死亡率仍然很高。因此，确定新的治疗方案势在必行。在本研究中，我们调查了代谢物核糖醇是否能增强紫草素在体外对乳腺癌的细胞毒性作用。在此，我们筛选了一组针对乳腺癌能量代谢的小分子。研究结果表明，核糖醇可增强紫草素的生长抑制作用，具有显著的协同作用。与紫草素单药治疗组（38%）相比，联合治疗组检测到凋亡细胞百分比显著（<0.01）增加（56%）。与未处理的细胞相比，核糖醇和紫草素联合治疗导致细胞增殖显著停滞（40%）（<0.01），并诱导细胞凋亡。这与p53上调（<0.05）以及c-Myc（<0.01）、Bcl-xL（<0.001）和Mcl-1（<0.05）下调有关。代谢组学分析支持这样的前提，即抑制瓦尔堡效应参与了紫草素诱导的细胞死亡，核糖醇处理导致的糖酵解和三羧酸（TCA）循环失调可能进一步增强了这种作用。总之，本研究表明，代谢物核糖醇在体外能选择性增强紫草素介导的对乳腺癌的细胞毒性作用。
