apratoxin A

Apratoxin A, a cyanobacterial metabolite, mediates antiproliferative activity through the induction of G1 cell cycle arrest and an apoptotic cascade. Apratoxin A associates with Hsp70/Hsc70 to promote the degradation of Hsp90 client proteins. Apratoxin A can specifically bind the Sec61 complex[1][2][3].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Signaling Pathways >> Cell Cycle/DNA Damage >> HSP

HSP70

HSP90

Apratoxin A (5, 50 nM; 24, 48 小时) 诱导 G1 细胞周期停滞和细胞凋亡。Apratoxin A 在酵母细胞中没有表现出任何生长抑制活性[1]。 Apratoxin A (50 nM; 1-24 小时) 抑制 STAT3 的 Tyr705 磷酸化[1]。 Cell Cycle Analysis[1] Cell Line: U2OS cells Concentration: 5, 50 nM Incubation Time: 24, 48 h Result: Resulted in an accumulation of cells harboring 2N (diploid) content of chromo-somes , suggesting G1-phase cell cycle arrest. Showed a complete block in cell cycle progression with 5 nM for 48 h. Apoptosis Analysis[1] Cell Line: U2OS cells Concentration: 50 nM Incubation Time: 0-48 h Result: A sub-G1 population emerged 50 nM, suggesting cellular apoptosis. Had 20-fold higher caspase-3 activity after 48 h. Western Blot Analysis[1] Cell Line: U2OS cells Concentration: 50 nM Incubation Time: 1, 4, 12, 24 h Result: had no effect on phosphorylation of Ser727 , but strongly inhibited constitutive phosphorylation at Tyr705 of STAT3.

Apratoxin A (0.5-1 mg/kg; 静脉给药; 每 7 天一次; BxPC-3 T1 模型 2 次; A549 模型 3 次) 具有剂量依赖性抗癌活性[2]。 Apratoxin A (1 mg/kg; 静脉注射) 具有高分布容积 (Vss=19.31 L/kg) 和中等半衰期 (11.57 小时)[2]。 Animal Model: 6-week old female NCr nu/nu mice with BxPC-3 T1 or A549 cells[1] Dosage: 0.5, 0.75, 1 mg/kg Administration: IV; every 7 days; for 2 total doses(BxPC-3 T1 study) or 3 doses (A549 study) Result: For BxPC3 T1 model, both 1 mg/kg and 0.75 mg/kg were found to exceed the MTD with a treated versus vehicle control effect on tumor size (T/C ratio) of 53% and 41%, respectively. It induced severe body weight loss right after first dose in both 1 mg/kg and 0.75 mg/kg. In the A549 model, 0.6 mg/kg, 0.5 mg/kg, and 0.4 mg/kg showed T/C ratios of 30%, 24%, and 41%, respectively. Animal Model: Athymic (NCr nu/nu) mice with A549 tumor cells[2] Dosage: 1 mg/kg Administration: IV Result: Showed a high volume of distribution (Vss=19.31 L/kg) and moderate half-life (11.57 hours).

[1]. Hendrik Luesch, et al. A functional genomics approach to the mode of action of apratoxin A. Nat Chem Biol. 2006 Mar;2(3):158-67.  

[2]. Kuan-Chun Huang, et al. Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61. Mol Cancer Ther. 2016 Jun;15(6):1208-16.  

[3]. Shensi Shen, et al. Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy.J Cell Biol. 2009 May 18;185(4):629-39.