Pifithrin-μ

Inhibitor of p53-mediated apoptosis

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10mg

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货号: ajci6372
CAS: 64984-31-2
别名: NSC 303580
分子式: C8H7NO2S
分子量: 181.21
纯度: >98%
溶解度: ≥ 18.1mg/mL in DMSO, ≥ 93.8 mg/mL in EtOH
储存: Store at -20°C,stored under nitrogen
库存: 现货

Background

Pifithrin-μ is a potent inhibitor of? p53 binding and p53-mediated apoptosis with Kd value of 0.82 mM in vitro[1].
The p53 is encoded in humans by the TP53 gene. The molecular mass of p53 is 53 KD. The p53 has the function of regulating the cell cycle, thus, it functions as preventing cancer, a tumor suppressor. The p53 plays an important role in apoptosis, inhibition of angiogenesis and genomic stability by activating DNA repair proteins, arresting cell growth though holding the cell cycle and initiating apoptosis. p53 becomes activated in response to DNA damage, osmotic shock, oxidative stress or other myriad stressors. Activated p53 activates the expression of several genes by binding DNA including p21. p21 binds to the G1-S/CDK complexes which is an important molecules for the G1/S transition, then causes cell cycle arrest. The increasing amount of p53 may be a solution for prevention of tumors spreading or treatment of them[1].
Pifithrin-μis a cell-permeable inhibitor of p53-binding and p53-mediated apoptosis. Pifithrin-μdirectly inhibits that p53 binds to mitochondria. Pifithrin-μ also inhibits p53 binds to Bcl-2 and Bcl-xL proteins. PFT-μbinds both Bcl-xL and p53 with Kd = 0.80 mM and 0.82 mM respectively.[1] Pifithrin-μ reduces apoptosis which triggered by nutlin-3 in ML-1 cells at 25μM [2]. Pifithrin-μ also selectively inhibits heat shock protein 70 (HSP 70) activity.
Pre-treatment with Pifithrin-μcan rescue primary thymocytes from γ-irradiation? or DNA damaging agents in mice.[2]?? ?
参考文献:
[1].?? ?Hagn F, Klein C, Demmer O, Marchenko N, Vaseva A, Moll UM, Kessler H: BclxL changes conformation upon binding to wild-type but not mutant p53 DNA binding domain. J Biol Chem 2010, 285(5):3439-3450.
[2].?? ?Vaseva AV, Marchenko ND, Moll UM: The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells. Cell Cycle 2009, 8(11):1711-1719.

Protocol

Cell experiment:

The cell viability is determined by the Cell Counting Kit-8 assay. Briefly, A549 and H460 cells are incubated in 96-well plates at a density of 5 × 103 per 100 μL of culture medium overnight. After treated with indicated concentration of Pifithrin-μ for 24 and 48 h, 10 μL of tetrazolium substrate are added to each well of the plate. After incubation at 37°C for 1 h, the absorbance is recorded at a wavelength of 450 nm using a microplate reader. Each experiment is determined in triplicate and repeated at least three times[2].

Animal experiment:

Mice[2]A549 cells (1 × 107) are suspended in Matrigel and inoculated subcutaneously into the mice. Twelve mice bearing evident tumors are arbitrarily assigned to PBS control group and Pifithrin-μ treatment groups (six mice per group). When tumors reach a size of ～5×5 mm2, mice are treated with either a single of intraperitoneal injection of Pifithrin-μ (20 mg/kg) or PBS every two days. After 3-week treatment, mice are euthanized with carbon dioxide. Tumor burdens are evaluated by measuring body weight, tumor weight, and tumor volume. Tumor volume is determined as 0.5 × length × width2. Tumor samples are collected and fixed in 10% neutral buffered formalin. Hematoxylin and eosin staining and immunohistochemistry for histological analysis of tumor samples are measured[2].

参考文献:

[1]. Strom E, et al. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol. 2006 Sep;2(9):474-9. Epub 2006 Jul 23.
[2]. Zhou Y, et al. Pifithrin-μ is efficacious against non-small cell lung cancer via inhibition of heat shock protein 70. Oncol Rep. 2017 Jan;37(1):313-322.
[3]. Glas M, et al. Neuroprotection with the P53-Inhibitor Pifithrin-μ after Cardiac Arrest in a Rodent Model. Shock. 2018 Feb;49(2):229-234.