Many cancer patients still lack effective treatments, and pre-existing or acquired resistance limits the clinical benefit of even the most advanced medicines. Recently, much attention has been given to the role of metabolism in cancer, expanding from the Warburg effect to highlight unique patterns that, in turn, may improve diagnostic and therapeutic approaches. Our recent metabolomics study revealed that ribitol can alter glycolysis in breast cancer cells. In the current study, we investigate the combinatorial effects of ribitol with several other anticancer drugs (chrysin, lonidamine, GSK2837808A, CB-839, JQ1, and shikonin) in various breast cancer cells (MDA-MB-231, MCF-7, and T-47D). The combination of ribitol with JQ1 synergistically inhibited the proliferation and migration of breast cancer cells cell-type dependently, only observed in the triple-negative MDA-MB-231 breast cancer cells. This synergy is associated with the differential effects of the 2 compounds on expression of the genes involved in cell survival and death, specifically downregulation in c-Myc and other anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), but upregulation in p53 and cytochrome C levels. Glycolysis is differentially altered, with significant downregulation of glucose-6-phosphate and lactate by ribitol and JQ1, respectively. The overall effect of the combined treatment on metabolism and apoptosis-related genes results in significant synergy in the inhibition of cell growth and induction of apoptosis. Given the fact that ribitol is a metabolite with limited side effects, a combined therapy is highly desirable with relative ease to apply in the clinic for treating an appropriate cancer population. Our results also emphasize that, similar to traditional drug development, the therapeutic potential of targeting metabolism for cancer treatment may only be achieved in combination with other drugs and requires the identification of a specific cancer population. The desire to apply metabolomic intervention to a large scope of cancer types may be one of the reasons identification of this class of drugs in a clinical trial setting has been delayed.
目前许多癌症患者仍缺乏有效治疗手段，既存性或获得性耐药限制了最先进药物的临床获益。近年来，代谢在癌症中的作用备受关注，研究范围已从Warburg效应扩展到独特的代谢模式，这些发现可能改善诊断和治疗方法。我们最近的代谢组学研究表明，核糖醇可改变乳腺癌细胞的糖酵解过程。本研究探讨了核糖醇与多种抗癌药物（白杨素、氯尼达明、GSK2837808A、CB-839、JQ1及紫草素）在不同乳腺癌细胞系（MDA-MB-231、MCF-7和T-47D）中的联合效应。核糖醇与JQ1的联合应用在三阴性乳腺癌细胞MDA-MB-231中表现出细胞类型依赖性的协同抑制作用，能显著抑制细胞增殖与迁移。这种协同作用与两种化合物对细胞存活和死亡相关基因表达的差异调控有关：特异性下调c-Myc及其他抗凋亡蛋白（Bcl-2、Bcl-xL、Mcl-1），同时上调p53和细胞色素C水平。糖酵解过程呈现差异化改变，核糖醇显著下调葡萄糖-6-磷酸水平，而JQ1则显著降低乳酸生成。联合治疗通过对代谢和凋亡相关基因的整体调控，在抑制细胞生长和诱导细胞凋亡方面产生显著协同效应。鉴于核糖醇作为代谢物具有副作用有限的特点，这种联合疗法在临床上治疗特定癌症群体时具有较高的应用价值与便捷性。研究结果同时强调，与传统药物研发类似，靶向代谢的癌症治疗潜力可能需要联合其他药物才能实现，且需明确特定癌症亚群。试图将代谢干预广泛适用于多种癌症类型的愿景，可能是此类药物在临床试验中进展迟缓的原因之一。
Metabolic Reprogramming by Ribitol Expands the Therapeutic Window of BETi JQ1 against Breast Cancer
肿瘤(癌症)患者之家