Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
BMC Cancer. 2021 Apr 30;21(1):481. doi: 10.1186/s12885-021-08186-9.
One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms.
The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells.
The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment.
Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.
癌症治疗的一个关键方法是药物联合治疗。药物联合治疗可以帮助减少剂量，从而减少副作用。此外，降低了药物耐药的可能性。在过去的几十年中，已经描述了肿瘤代谢的明显改变，但代谢尚未在临床癌症治疗中得到靶向。最近，我们发现了丙二酸盐（DCA），一种丙酮酸脱氢酶激酶抑制剂，和 HIF-1α 抑制剂 PX-478 之间协同作用的证据。在这项研究中，我们旨在分析不同癌症类型细胞系中的这种协同作用，并确定潜在的生化机制。
使用 SRB 测定法评估了单一药物及其组合的剂量依赖性抗增殖作用。通过 FACS、Western blot 和 HPLC 分析来研究活性氧水平、细胞凋亡和细胞周期的变化。此外，还对 DCA 处理的 MCF-7 细胞进行了实时代谢分析（ Seahorse ）。
在所有测试的八种癌细胞系中，DCA 和 PX-478 的联合使用产生了协同作用，包括结直肠癌、肺癌、乳腺癌、宫颈癌、肝癌和脑癌。活性氧的产生和细胞凋亡在这种协同作用中起着重要作用。此外，联合治疗抑制了细胞增殖。
在这里，我们发现这些靶向肿瘤代谢的化合物在所有测试的癌细胞系中表现出很强的协同作用。因此，我们强烈建议将这两种化合物联合使用，以推进体内转化和临床试验。
