Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de México, México.
Curr Med Chem. 2022;29(15):2719-2735. doi: 10.2174/0929867328666211005124015.
The major hurdles for successful cancer treatment are drug resistance and invasiveness developed by breast cancer stem cells (BCSC).
As these two processes are highly energy-dependent, the identification of the main ATP supplier required for stem cell viability may result advantageous in the design of new therapeutic strategies to deter malignant carcinomas.
The energy metabolism (glycolysis and oxidative phosphorylation, OxPhos) was systematically analyzed by assessing relevant protein contents, enzyme activities, and pathway fluxes in BCSC. Once identified as the main ATP supplier, selective energy inhibitors and canonical breast cancer drugs were used to block stem cell viability and metastatic properties.
OxPhos and glycolytic protein contents, as well as HK and LDH activities were several times higher in BCSC than in their parental line, MCF-7 cells. However, CS, GDH, COX activities, and both energy metabolism pathway fluxes were significantly lower (38-86%) in BCSC than in MCF-7 cells. OxPhos was the main ATP provider (>85%) in BCSC. Accordingly, oligomycin (a specific and potent canonical OxPhos inhibitor) and other non-canonical drugs with inhibitory effect on OxPhos (celecoxib, dimethylcelecoxib) significantly decreased BCSC viability, levels of epithelial-mesenchymal transition proteins, invasiveness, and induced ROS over-production, with IC values ranging from 1 to 20 μM in 24 h treatment. In contrast, glycolytic inhibitors (gossypol, iodoacetic acid, 3-bromopyruvate, 2-deoxyglucose) and canonical chemotherapeutic drugs (paclitaxel, doxorubicin, cisplatin) were much less effective against BCSC viability (IC> 100 μM).
These results indicated that the use of some NSAIDs may be a promising alternative therapeutic strategy to target BCSC.
癌症治疗的主要障碍是乳腺癌干细胞（BCSC）产生的耐药性和侵袭性。
由于这两个过程高度依赖能量，因此确定干细胞存活所需的主要 ATP 供应源可能有利于设计新的治疗策略来阻止恶性癌。
通过评估 BCSC 中的相关蛋白含量、酶活性和途径通量，系统地分析能量代谢（糖酵解和氧化磷酸化，OxPhos）。一旦被确定为主要的 ATP 供应源，就会使用选择性能量抑制剂和经典的乳腺癌药物来阻断干细胞的存活和转移特性。
BCSC 中的 OxPhos 和糖酵解蛋白含量以及 HK 和 LDH 活性比其亲本系 MCF-7 细胞高几倍。然而，CS、GDH、COX 活性以及两种能量代谢途径通量在 BCSC 中均显著低于 MCF-7 细胞（38-86%）。OxPhos 是 BCSC 中的主要 ATP 提供者（>85%）。因此，寡霉素（一种特异性和有效的经典 OxPhos 抑制剂）和其他具有抑制 OxPhos 作用的非经典药物（塞来昔布、二甲塞来昔布）显著降低了 BCSC 的活力、上皮-间充质转化蛋白水平、侵袭性，并诱导 ROS 过度产生，在 24 小时处理中，IC 值范围为 1 至 20 μM。相比之下，糖酵解抑制剂（棉酚、碘乙酸、3-溴丙酮酸、2-脱氧葡萄糖）和经典化疗药物（紫杉醇、多柔比星、顺铂）对 BCSC 活力的作用要小得多（IC>100 μM）。
这些结果表明，使用一些非甾体抗炎药可能是一种有前途的针对 BCSC 的治疗策略替代方案。
