Liarozole dihydrochloride is a P-450 inhibitor and retinoic acid (RA) metabolizing blocking agent inhibits RA metabolism and thereby increases intracellular RA levels in cells that actively produce RA. Liarozole has been used in the treatment of a variety of conditions characterized by extracellular matrix (ECM) overproduction such as ichthyosis[1].
IC50 values for P-450 Inhibitors Liarozole was determined as 4.2 μM, using male rat hepatic microsomes and 3uM retinoic acid as substrate[2]. Liarozole combination with ATRA potently increased the ability of ATRA to induce proline isomerase (Pin1) degradation.Pin1 knockdown suppresses cell proliferation in various human HCC cell lines. When the concentration of ATRA was fixed at 10?μM, Pin1 was degraded in a dose dependent manner depending on increasing concentrations of liarozole, with IC50 ~24.5?μM[3]
The cumulative tumor growth was significantly slower in Liarozole compared to the control group (p = 0.0001). Both liarozole and tamoxifen when given alone demonstrated anti-tumor effects. However, while tamoxifen lead to tumor shrinkage, liarozole was only able to stop tumor growth. When given in combination, liarozole (80 mg/kg) plus tamoxifen (100 mg/kg) was more effective than liarozole alone (p = 0.0001). There were no significant differences between the two doses of liarozole either when given alone (p = 0.49) or in combination with tamoxifen (p = 0.8)[4]
References:
[1]. Levy G, Malik M, et al. Liarozole inhibits transforming growth factor-β3--mediated extracellular matrix formation in human three-dimensional leiomyoma cultures. Fertil Steril. 2014 Jul;102(1):272-281.e2.
[2]. Ahmad M. Study on cytochrome p-450 dependent retinoic Acid metabolism and its inhibitors as potential agents for cancer therapy. Sci Pharm. 2011 Oct-Dec;79(4):921-35.
[3]. Liao XH, Zhang AL, et al.Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways. Sci Rep. 2017 Mar 6;7:43639.
[4]. Goss PE, Strasser-Weippl K, et al.Effects of liarozole fumarate (R85246) in combination with tamoxifen on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model. BMC Cancer. 2007 Jan 31;7:26.
Liarozole dihydrochloride 是一种 P-450 抑制剂，视黄酸 (RA) 代谢阻断剂可抑制 RA 代谢，从而增加活跃产生 RA 的细胞中的细胞内 RA 水平。利罗唑已用于治疗多种以细胞外基质 (ECM) 过度生成为特征的病症，例如鱼鳞病[1]。
IC50 值为 4.2 μM，使用雄性大鼠肝微粒体和 3uM 视黄酸作为底物[2]。 Liarozole 与 ATRA 的组合有效地增加了 ATRA 诱导脯氨酸异构酶 (Pin1) 降解的能力。Pin1 敲低抑制了各种人类 HCC 细胞系中的细胞增殖。当 ATRA 浓度固定在 10μM 时，Pin1 以剂量依赖的方式降解，这取决于利罗唑浓度的增加，IC50 ~24.5μM[3] /p>\n
与对照组相比，利罗唑的累积肿瘤生长显着减慢 (p = 0.0001)。单独给予利罗唑和他莫昔芬均显示出抗肿瘤作用。然而，虽然他莫昔芬导致肿瘤缩小，但利罗唑只能阻止肿瘤生长。联用时，利罗唑 (80 mg/kg) 加他莫昔芬 (100 mg/kg) 比单独使用利罗唑更有效 (p = 0.0001)。无论是单独给药 (p = 0.49) 还是与他莫昔芬联合给药 (p = 0.8)，两种剂量的利罗唑都没有显着差异[4]
与对照组相比，利罗唑的累积肿瘤生长显着减慢 (p = 0.0001)。单独给予利罗唑和他莫昔芬均显示出抗肿瘤作用。然而，虽然他莫昔芬导致肿瘤缩小，但利罗唑只能阻止肿瘤生长。联用时，利罗唑 (80 mg/kg) 加他莫昔芬 (100 mg/kg) 比单独使用利罗唑更有效 (p = 0.0001)。无论是单独给药 (p = 0.49) 还是与他莫昔芬联合给药 (p = 0.8)，两种剂量的利罗唑都没有显着差异[4]