Fluorizoline
目录号 : GC62167
Fluorizoline 选择性地直接结合到 prohibitin 1 (PHB1) 和 2 (PHB2)，并诱导凋亡。Fluorizoline 通过上调 NOXA 和 BIM 降低慢性淋巴细胞性白血病 (CLL) 细胞的活力。Fluorizoline 以 p53 非依赖性方式发挥抗肿瘤作用。
Cas No.:1362243-70-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Fluorizoline selectively and directly binds to prohibitin 1 (PHB1) and 2 (PHB2), and induces apoptosis. Fluorizoline reduces chronic lymphocytic leukemia (CLL) cell viability through the upregulation of NOXA and BIM. Fluorizoline exerts antitumor action in a p53-independent manner[1].
Fluorizoline (1.25-20 μM; 24 hours) induces apoptosis in primary CLL cells ex vivo[1]. Fluorizoline (5-10 μM; 48 hours) causes an increase of NOXA protein levels[1]. Fluorizoline reduces the percentage of viable normal B and T cells (48.6% and 82.8% of viable cells at 24 hours of treatment with 10 μM Fluorizoline in normal CD19+ and CD3+ populations, respectively) with mean EC50 values of 10.9 μM and 19.1 μM at 24 hours for normal B and T cells, respectively[1].
Fluorizoline (15 mg/kg; ip; three times a week for five weeks) becomes very rapidly (3 weeks) leukemic, as reflected by the increase in the percentage and the number of CD5+CD19+ CLL cells in the blood in 6-week-old recipient C57BL/6 Eμ-TCL1 mouse model of CLL. Fluorizoline does not induce apoptosis in vivo. Fluorizoline does not control disease development in the spleen as indicated by enlarged spleens[2].
[1]. Ana M Cosialls, et al. The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax. Haematologica. 2017 Sep;102(9):1587-1593.
[2]. Marina Wierz, et al. The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells ex vivo but fails to prevent leukemia development in a murine model. Haematologica. 2018 Apr;103(4):e154-e157.
| Cas No. | 1362243-70-6 | SDF | |
| 分子式 | C15H8Cl2F3NS | 分子量 | 362.2 |
| 溶解度 | DMSO : 50 mg/mL (138.05 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7609 mL | 13.8045 mL | 27.6091 mL |
| 5 mM | 0.5522 mL | 2.7609 mL | 5.5218 mL |
| 10 mM | 0.2761 mL | 1.3805 mL | 2.7609 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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Fluorizoline-induced apoptosis requires prohibitins in nematodes and human cells
Apoptosis 2021 Feb;26(1-2):83-95.PMID:33387147DOI:10.1007/s10495-020-01651-z.
We previously showed that Fluorizoline, a fluorinated thiazoline compound, binds to both subunits of the mitochondrial prohibitin (PHB) complex, PHB1 and PHB2, being the expression of these proteins required for fluorizoline-induced apoptosis in mouse embryonic fibroblasts. To investigate the conservation of this apoptotic mechanism, we studied the effect of PHB downregulation on Fluorizoline activity on two human cell lines, HEK293T and U2OS. Then, we asked whether PHBs mediate the effect of Fluorizoline in a multicellular organism. Interestingly, reduced levels of PHBs in the human cells impaired the induction of apoptosis by Fluorizoline. We observed that Fluorizoline has a detrimental dose-dependent effect on the development and survival of the nematode model Caenorhabditis elegans. Besides, such effects of Fluorizoline treatment in living nematodes were absent in PHB mutants. Finally, we further explored the apoptotic pathway triggered by Fluorizoline in human cell lines. We found that the BH3-only proteins NOXA, BIM and PUMA participate in fluorizoline-induced apoptosis and that the induction of NOXA and PUMA is dependent on PHB expression.
Fluorizoline Blocks the Interaction between Prohibitin-2 and γ-Glutamylcyclotransferase and Induces p21Waf1/Cip1 Expression in MCF7 Breast Cancer Cells
Mol Pharmacol 2022 Feb;101(2):78-86.PMID:34862308DOI:10.1124/molpharm.121.000334.
Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21Waf1/Cip (p21) gene in the nucleus. The cytotoxic drug Fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of Fluorizoline is not fully elucidated. In the present study, we first show that Fluorizoline induces p21 expression in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with Fluorizoline suppressed proliferation and prevented cells from entering into the DNA synthesis phase. Knockdown of p21 rescued the suppressed proliferation, indicating that Fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by Fluorizoline and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with Fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with Fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells. SIGNIFICANCE STATEMENT: This study shows that Fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that Fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins.
Development of Fluorizoline analogues as prohibitin ligands that modulate C-RAF signaling, p21 expression and melanogenesis
Eur J Med Chem 2022 Nov 15;242:114635.PMID:35988448DOI:10.1016/j.ejmech.2022.114635.
Fluorizoline is a cytotoxic trifluorothiazoline that targets the scaffold proteins prohibitins-1 and -2 (PHB1/2) to inhibit the kinase C-RAF and promote the expression of the cyclin-dependent kinase inhibitor p21 to induce cancer cell death. In melanocytes, Fluorizoline also induces the synthesis of melanin. Herein we report the first structural requirement of Fluorizoline analogues for these activities. We identified in particular some compounds that display enhanced anti-C-RAF and anti-MEK activities, and a higher cytotoxicity in HeLa cells compared to Fluorizoline. These results provide a foundation for further optimization of PHB ligands for the treatment of cancers. We also discovered an analogue of Fluorizoline that displays pharmacological effects opposed to those of Fluorizoline and that can be used as a chemical tool to explore PHB signaling in cancers and other diseases.
The prohibitin-binding compound Fluorizoline inhibits mitophagy in cancer cells
Oncogenesis 2021 Sep 27;10(9):64.PMID:34580273DOI:10.1038/s41389-021-00352-9.
Fluorizoline is a prohibitin-binding compound that triggers apoptosis in several cell lines from murine and human origin, as well as in primary cells from hematologic malignancies by inducing the integrated stress response and ER stress. Recently, it was described that PHB (Prohibitin) 1 and 2 are crucial mitophagy receptors involved in mediating the autophagic degradation of mitochondria. We measured mitophagy in HeLa cells expressing Parkin and in A549, a lung cancer cell line that can undergo mitophagy in a Parkin-independent manner, and we demonstrated that both Fluorizoline and rocaglamide A, another PHB-binding molecule, inhibit CCCP- and OA-induced mitophagy. Moreover, we demonstrated that PHBs are mediating Parkin-dependent mitophagy. In conclusion, besides being a potent pro-apoptotic compound, we present Fluorizoline as a promising new mitophagy modulator that could be used as anticancer agent.
The BCL-2 family members NOXA and BIM mediate fluorizoline-induced apoptosis in multiple myeloma cells
Biochem Pharmacol 2020 Oct;180:114198.PMID:32798467DOI:10.1016/j.bcp.2020.114198.
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In this study, we have assessed the pro-apoptotic effect of Fluorizoline in 3 different multiple myeloma cell lines and 12 primary samples obtained from treatment-naïve multiple myeloma patients. Fluorizoline induced apoptosis in both multiple myeloma cell lines and primary samples at concentrations in the low micromolar range. All primary samples were sensitive to Fluorizoline. Moreover, Fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. Finally, NOXA-depletion by CRISPR/Cas9 in cells that do not express BIM conferred resistance to fluorizoline-induced apoptosis in multiple myeloma cells. These results suggest that targeting prohibitins could be a new therapeutic strategy for myeloma multiple.