3α-Aminocholestane is an inhibitor of Src homology 2 domain-containing inositol 5'-phosphatase 1 (SHIP1) and a cholesterol derivative with an IC50 of approximately 10μM[1]. SHIP1 negatively regulates various intracellular signaling pathways. By inhibiting the activity of SHIP1, 3α-Aminocholestane interferes with related signal transduction and affects cellular physiological functions[2]. 3α-Aminocholestane has shown potential value in a variety of tumor-related studies, including liver cancer, lung cancer, and breast cancer[3].
In vitro, treatment of K562, KG1, and C14908 cells with 3α-Aminocholestane (0-15μM) for 36 hours reduced the viability of SHIP1-expressing human acute myeloid leukemia cell line KG-1 and mouse leukemia cell line C14908, inhibited their growth, and promoted apoptosis; however, it had no significant effect on K562 leukemia cells that do not express SHIP1[4]. Treatment of U266, RPMI8226, and OPM2 cells with 3α-Aminocholestane (0-12.5μM) for 48 hours resulted in differential responses such as cell cycle arrest, apoptosis, and autophagy in different multiple myeloma cells by affecting the PI3K-Akt signaling pathway[5].
In vivo, treatment of collagen-induced arthritis (CIA) model mice with 3α-Aminocholestane (60μM) via intraperitoneal injection reduced the infiltration of inflammatory cells in the joints of mice and alleviated cartilage damage and bone erosion[6]. Treatment of BALB/c mice with 3α-Aminocholestane (60μM/day) for seven days increased anti-leishmanial activity, but reduced the production of leishmanial precytokines and decreased the parasite load of L.major and L.donovani infections[7].
References:
[1] Pacherille AM, Viernes DR, Pedicone C, et al. Aminocholestane and Aminoandrostane Inhibitors of the SH2 Domain-Containing Inositol 5'-Phosphatase (SHIP). ChemMedChem 2025, 20(8):e202400597.
[2] Müller SM, Jücker M The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases. Int J Mol Sci 2024, 25(10).
[3] Pedicone C, Meyer ST, Chisholm JD, et al. Targeting SHIP1 and SHIP2 in Cancer. Cancers (Basel) 2021, 13(4).
[4] Brooks R, Fuhler GM, Iyer S, et al. SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. J Immunol 2010, 184(7):3582-3589.
[5] Fuhler GM, Brooks R, Toms B, et al. Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Mol Med 2012, 18(1):65-75.
[6] So EY, Sun C, Wu KQ, et al. Inhibition of lipid phosphatase SHIP1 expands myeloid-derived suppressor cells and attenuates rheumatoid arthritis in mice. Am J Physiol Cell Physiol 2021, 321(3):C569-c584.
[7] Chowdhury BP, Das S, Bodhale N, et al. SHIP1 inhibition via 3-alpha-amino-cholestane enhances protection against Leishmania infection. Cytokine 2023, 171:156373.
3α-Aminocholestane是肌醇-5'-磷酸酶1（SHIP1）的抑制剂，属于胆固醇衍生物，其IC50约为10μM[1]。SHIP1负向调节多种细胞内信号通路，3α-Aminocholestane通过抑制其活性，干扰相关信号传导，影响细胞生理功能[2]。3α-Aminocholestane在多种肿瘤相关研究中显示出潜在价值，包括肝癌、肺癌、乳腺癌等[3]。
在体外，3α-Aminocholestane（0-15μM）分别处理K562、KG1和C14908细胞36小时，降低表达 SHIP1的人急性髓系白血病细胞系KG-1、小鼠白血病细胞系C1498细胞的活力，抑制其生长并促进凋亡；而对不表达SHIP1的K562白血病细胞，则无明显影响 [4]。使用3α-Aminocholestane（0-12.5μM）处理U266、RPMI8226和OPM2细胞48h，通过影响PI3K-Akt信号通路，导致不同多发性骨髓瘤细胞出现细胞周期停滞、凋亡及自噬等差异反应[5]。
在体内，3α-Aminocholestane（60μM）通过腹腔注射治疗胶原诱导性关节炎（CIA）模型小鼠，可减少小鼠关节中的炎症细胞浸润，减轻软骨损伤和骨侵蚀[6]。3α-Aminocholestane（60μM/天）治疗BALB/c小鼠七天可增加抗利什曼原虫，但减少利什曼原虫前细胞因子的产生，并减少L. major和L. donovani感染的寄生虫负荷[7]。