ACT-PFK-158 is a novel anti-cancer agent that inhibits glucose uptake in cancer cells. The primary objective of the study will be to determine the maximum tolerated dose (MTD) and to describe any dose limiting toxicity. The secondary objectives of the study will be to determine the safety profile of the drug, to determine the pharmacokinetic profile, to identify any anti-tumor activity, and to determine the pharmacodynamic profile of ACT-PFK-158.

Start Date01 Mar 2014

Sponsor / Collaborator

Advanced Cancer Therapeutics LLC

100 Clinical Results associated with PFKFB3

100 Translational Medicine associated with PFKFB3

0 Patents (Medical) associated with PFKFB3

726

Literatures (Medical) associated with PFKFB3

01 Apr 2025·Journal of Hazardous Materials

F-53B disrupts energy metabolism by inhibiting the V-ATPase-AMPK axis in neuronal cells

Article

Author: Zhang, Yue ; Ding, Xueman ; Zhang, Jingjing ; Ma, Runjiang ; Qin, Wenqi ; Niu, Qiang ; Yan, Chulin ; Keerman, Mulatibieke ; Li, Tingting ; Wang, Chun ; Liu, Li

6:2 chloro-polyfluorooctane ether sulfonate (F-53B) is considered neurotoxic, but its mechanisms remain unclear. This study aimed to investigate the toxic effects of F-53B on neuronal cells, focusing on the role of the V-ATPase-AMPK axis in the mechanism of abnormal energy metabolism. Mouse astrocytes (C8-D1A) and human neuroblastoma cells (SH-SY5Y) exposed to F-53B were used as in vitro models. Our findings demonstrated that F-53B inhibited the expression of V-ATPase B2 and reduced V-ATPase activity, leading to an increase in lysosomal pH, decreased expression of TRPML1, and lysosomal Ca^2 + accumulation. In turn, led to reduced the expression of CaMKK2 and phosphorylated AMPK (p-AMPK). Ultimately, mitochondria were damaged, evidenced by increased mitochondrial reactive oxygen species, mitochondrial membrane potential, and impaired mitochondrial oxidative phosphorylation, as shown by reduced NDUFS1 expression and diminished respiratory chain complex I activity. F-53B reduced the expression of the key glycolytic protein PFKFB3. Notably, V-ATPase B2 overexpression indirectly activates AMPK. Furthermore, resveratrol, an AMPK agonist, alleviates mitochondrial dysfunction and increases ATP production by promoting the recovery of mitochondria and glycolytic pathways. These findings elucidate a novel mechanism by which F-53B induces neurotoxicity through the V-ATPase-AMPK axis, and indicate V-ATPase and AMPK as potential therapeutic targets.

01 Mar 2025·Cellular Signalling

USP27 promotes glycolysis and hepatocellular carcinoma progression by stabilizing PFKFB3 through deubiquitination

Article

Author: Ning, Yinkuan ; Ouyang, Zhengsheng ; Yang, Yang ; Song, Dekun ; Li, Lai ; Xie, Longhui ; Xia, Wangning ; Liu, Xintao

Hepatocellular carcinoma (HCC) is associated with a dismal prognosis, primarily due to its high rates of metastasis and recurrence. Metabolic reprogramming, specifically enhanced glycolysis, is a prominent feature of cancer progression. This study identifies ubiquitin-specific peptidase 27 X-linked (USP27) as a significant regulator of glycolysis in HCC. We demonstrate that USP27 stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating tumor progression. Furthermore, we reveal that CTCF, a well-known transcription factor, directly binds to the USP27 promoter and upregulates its expression, thereby establishing a connection between transcriptional regulation and metabolic reprogramming in HCC. Knockdown of USP27 or CTCF in HCC cells considerably decreased glycolysis and proliferation, while overexpression had the opposite effect. In vivo studies confirmed that USP27 knockdown suppresses HCC growth and metastasis. Our findings establish the CTCF/USP27/PFKFB3 axis as a novel mechanism driving HCC progression through glycolysis, indicating that targeting this pathway could offer new therapeutic opportunities. These results provide valuable insights into the molecular mechanisms underlying HCC and emphasize the potential of targeting USP27-mediated metabolic pathways as a strategy for cancer treatment.

01 Feb 2025·Microbial Pathogenesis

Enhanced autophagy and cholesterol efflux in mouse mesenchymal stem cells infected with H37Rv compared to H37Ra

Article

Author: Yin, Yan ; Chen, Shichao ; Xing, Yanchun ; Yang, Hong ; Chen, Jianxia ; Li, Heng ; Cao, Wei

Autophagy, metabolism, and associated signaling pathways play critical roles in bacterial survival within mammalian cells and influence the immunopathogenesis of infections. Mesenchymal stem cells (MSCs) are important host cells during Mycobacterium tuberculosis (Mtb) infection, yet how autophagy, metabolism, and related pathways are modulated in MSCs infected with the virulent H37Rv or the attenuated H37Ra strain of Mtb remains poorly understood. In this study, we utilized RNA-Seq screening, qRT-PCR, and Western Blotting to investigate the differences in these processes between H37Rv and H37Ra infections. Our results show that, at early time points (no more than 24h), infection with H37Rv significantly increased the expression of TlLR2, Prkaa2, and Prkaa2 phosphorylation in MSCs compared with H37Ra infection. Further analysis revealed that H37Rv infection induced a stronger autophagic response (evidenced by increased Atg9b and LC3II/LC3I) through the TLR2-AMP-AMPK pathway than H37Ra infection. Despite these differences in autophagy, there was no statistically significant difference in bacillary loads, suggesting that, in addition to autophagy, other factors such as apoptosis and immune-inflammatory responses may also regulate Mtb growth in MSCs. Additionally, the metabolic analysis showed that H37Rv infection led to increased expression of SLC2A3, PFKFB3, HK1, and ABCA1 in MSCs compared to H37Ra infection. These findings confirm that, during the early stages of infection, H37Rv induces enhanced autophagy, glucose metabolism, and cholesterol efflux through a more active TLR2-AMP-AMPK pathway than H37Ra. Therefore, MSCs may represent a novel target for the prevention and treatment of tuberculosis.

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