Bromopyruvate

Recurrent pregnancy loss (RPL) is a severe complication, and its risk is heightened by dysregulated trophoblast development. However, the underlying mechanisms remain unclear. Herein, we show that a portion of villous samples from patients with RPL display reduced hexokinase II (HK2) and Yes-associated protein 1 (YAP1) expression compared with healthy controls. Moreover, in human trophoblast stem (TS) cell models, blocking HK2 activities via exposure to 3-bromopyruvate markedly reduced cell proliferation and induced cell cycle arrest by regulating YAP1 phosphorylation and localization. This was partially reversed by the YAP signaling activator TT-10. Moreover, YAP1 contributes to aerobic glycolysis regulation by influencing HK2 activity. Together, these findings demonstrate an interplay between the Hippo/YAP1 pathway and glucose metabolism in placental trophoblast development and highlight an approach for RPL intervention.

Acute myeloid leukemia (AML) comprises a diverse group of blood cancers with varying genetic, phenotypic, and clinical traits, making development of targeted therapy challenging. Metabolic reprogramming in AML has been described as relevant for chemotherapy effectiveness. 3-Bromopyruvate (3-BP) is an anticancer agent that undermines energy metabolism of cancer cells. However, the effect of 3-BP in hematologic malignancies, such as AML, needs further investigation. Thus, we aimed to explore 3-BP as a chemo-sensitizing agent in AML. Different approaches of combining 3-BP with classical chemotherapy (daunorubicin and cytarabin) were tested in diverse AML cell lines. Cell sensitivity to the different drug combinations was analyzed by Trypan blue staining. The effect of pre-treatment with a non-toxic concentration of 3-BP was assessed on the AML cell metabolic profile (Western blot and immunofluorescence), mitochondrial activity (cytometry flow), and antioxidant capacity (colorimetric detection kit). KG-1 and MOLM13 cells showed increased sensitivity to chemotherapy (decreased EC₅₀ values) after exposure to a non-toxic concentration (5 μM) of 3-BP. In both cell lines, 5 μM 3-BP decreased glucose consumption without changing extracellular lactate levels. 5 μM 3-BP treatment increased reactive oxygen species levels and decreased cell antioxidant capacity by depleting reduced glutathione levels in both KG-1 and MOLM13 cells. Our results demonstrate that non-toxic concentrations of 3-BP enhance the effect of classical chemotherapy in AML cells through a pro-oxidant mechanism. These data unveiled a new approach for AML treatment, using 3-BP or other pro-oxidant agents as co-adjuvants of chemotherapy, subsiding chemotherapy-induced side effects.