HIF-1α is constitutively expressed subunit of HIF-1 mediating the cellular response to hypoxia, which can be rapidly degraded by the ubiquitin-26S proteasome pathway under conditions of normoxia. PX-478 target on HIF-1α, which can selectively inhibit the hypoxia-induced increase in HIF-1a protein. Treatment with PX-478 for 16h can inhibit nuclear HIF-1αprotein level in cell lines under hypoxic (1% O2, 5%CO2, 94% N2) compared with cells under normoxia (air, 5% CO2) with IC50 values for PC-3 prostate cancer cells of 3.9 ± 2.0 μM, MCF-7 breast cancer cells of 4.0 ± 2.0 μM, HT-29 colon cancer cells of 19.4 ± 5.0 μM, Panc-1 pancreatic cancer cells of 10.1 ± 1.9 μM and BxPC-3 pancreatic cancer cells of 15.3 ± 4.8 μM, without affection on levels of HIF-1βprotein. Meanwhile, PX-478 treatment also significantly decreased the activity of a HIF-1 (measured by transiently transfected HIF-1 reporter), as well as hypoxia-induced expression of VEGF, a HIF-1-regulated protein, in MCF-7 cells in a dose-dependent manner (0 - 25 μM, for 16h) but did not affect basal levels of VEGF formation under normoxic conditions[1]. Treatment with PX-478, i.p., at dose of 75 or 100 mg/kg/day repressed tumor growth in female SCID mice were implanted, s.c., with SHP-77 human small cell lung cancer cells. Also treatment with PX-478, i.p., at dose of 100mg/kg/day suppressed tumor growth in male SCID mice implanted s.c. with PC-3 prostate cancer cells[2]. Up to now, phase 1 studies of PX-478 treatment for advanced solid tumors and lymphoma have been completed (see https://www.clinicaltrials.gov/)
作用机制
The action of PX-478 on HIF-1αmay due to: 1. Modulation of HIF-1αubiquitination; 2. Inhibition on HIF-1α transcription; 3. Inhibition on HIF-1α translation.
PX-478·2HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BT-549 cells
30 µM
24 h
To evaluate the effect of PX-478 on BT-549 cell proliferation and M2 macrophage polarization, results showed that PX-478 inhibited cell proliferation and M2 polarization.
Clin Transl Med. 2024 Aug;14(8):e1763.
MDA-MB-231 (triple-negative breast cancer cells)
25 µM
24 h
To evaluate the cytotoxicity of PX-478 on triple-negative breast cancer cells, results showed that PX-478 combined with low-dose Doxo had a synergistic effect, significantly reducing cell viability.
Cancer Cell Int. 2023 Jul 5;23(1):133.
C4-2B cells
50 µM
24 h
PX-478 induced CC3 and CPARP levels in C4-2B cells, which were further enhanced when combined with enzalutamide
EMBO Mol Med. 2023 Jun 7;15(6):e17209.
DU-145 cells
50 µM
24 h
PX-478 induced CC3 and CPARP levels in DU-145 cells
EMBO Mol Med. 2023 Jun 7;15(6):e17209.
PC-3 cells
50 µM
24 h
PX-478 induced CC3 and CPARP levels in PC-3 cells
EMBO Mol Med. 2023 Jun 7;15(6):e17209.
C6 glioma cells
0.1 to 200 μM
24 h
PX-478 inhibited HIF-1-dependent GFP signaling in C6 cells with an IC50 value of 49.2 μM.
Mol Cancer Ther. 2009 Apr;8(4):947-58.
HN5 cells
25 μM
24 h
PX-478 inhibited HIF-1 protein expression and reduced VEGF secretion in HN5 cells under hypoxic conditions.
Mol Cancer Ther. 2009 Apr;8(4):947-58.
UMSCCA10 cells
25 μM
24 h
PX-478 inhibited HIF-1 protein expression and reduced VEGF secretion in UMSCCA10 cells under hypoxic conditions.
Mol Cancer Ther. 2009 Apr;8(4):947-58.
Panc-1 pancreatic cancer cells
25 μM
24 h
PX-478 provided direct radiosensitization in Panc-1 cells under hypoxic conditions.
Mol Cancer Ther. 2009 Apr;8(4):947-58.
PX-478·2HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Balb/c mice
4T1 breast cancer model
Intraperitoneal injection
30 mg/kg
Twice a week for 4 weeks
To evaluate the effect of PX-478 on breast cancer progression, results showed that PX-478 inhibited tumor growth and prolonged the survival time of mice.
Clin Transl Med. 2024 Aug;14(8):e1763.
Mice
Wild-type mice
Intraperitoneal injection
5 mg/kg
1 hour before each ethanol exposure, lasting for 6 hours
PX-478 partially suppressed binge alcohol-mediated increases in HIF-1 α and BNIP3, attenuated iNOS induction and subsequent nitrotyrosine formation, and partially blocked binge alcohol-induced hepatocyte apoptosis and plasma ALT elevation.
Free Radic Biol Med. 2014 Dec;77:183-94
Mice
Portal hypertension model
Oral gavage
5 mg/kg
Every other day, duration not specified
PX-478 alleviated PHT-mediated mitochondrial dysfunction and oxidative stress in the gastric mucosa, reversed mitochondrial morphological changes, and decreased ROS production.
Clin Transl Med. 2024 Apr;14(4):e1653
FVB mice
Intramuscular implantation model
Intraperitoneal injection
50 mg/kg
Every other day injection for 1 week or 2 weeks
To investigate the effect of HIF-1α inhibitor PX-478 on macrophage polarization and osteoclastogenesis in MG implants. The results showed that PX-478 significantly inhibited HIF-1α expression, macrophage polarization, and osteoclastogenesis in MG implants.
Adv Sci (Weinh). 2023 May;10(15):e2207224
Mice
Pten-deficient mouse model
Oral gavage
20 mg/kg
Once daily for 3 weeks
PX-478 treatment significantly reduced the proportion of adenocarcinoma in Pten-deficient mouse prostate tumors and induced apoptosis in tumor cells
EMBO Mol Med. 2023 Jun 7;15(6):e17209.
Nude mice
C6 and HN5 xenograft models
Oral
30 mg/kg
2 consecutive days
PX-478 significantly enhanced the inhibitory effect of single-dose irradiation on C6 and HN5 xenograft tumors in vivo, and achieved radiosensitization by inhibiting HIF-1-dependent tumor stromal adaptation.
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