Mithramycin A is an antibiotic isolated from S. grieseus [1]. As a selective inhibitor of specific protein 1 (Sp1), Mithramycin A binds to DNA sequences rich in GC, replacing the Sp1 transcription factor that binds to oncogenes, thereby inhibiting gene expression [2]. Mithramycin A has anti-tumor and neuroprotective effects [3].
In vitro, Mithramycin A (0-400nM, 24 hours) can dose-dependently inhibit the expression of GSTM2 protein in BFTC 905 and 5637 cells [4]. Mithramycin A (75μM; 24 hours) significantly increases the apoptosis of TNF-induced TF-1 cells, and the enhanced cytotoxicity of Mithramycin A on TNF occurs at the FADD level or its downstream position [5].
In vivo, Mithramycin A (0.2mg/kg/day; three times per week for 29 days; i.p.) significantly reduces the tumor volume of human cervical cancer cell xenograft mice and increases the number of TUNEL-positive cells in the tumor xenografts [6]. Mithramycin A (150μg/kg/day; 60 days; i.p.) treatment can effectively inhibit the Sp1 activation level in APPswe/PS1dE9 mice, significantly reduce the Aβ level and plaque load in the mouse brain, and reduce tau hyperphosphorylation, and increase synaptic markers [7].
References:
[1] Sleiman SF, Berlin J, Basso M, Karuppagounder SS, Rohr J, Ratan RR. Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration. Pharmaceuticals (Basel). 2011;4(8):1183-1195.
[2] Choi ES, Nam JS, Jung JY, Cho NP, Cho SD. Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer. Sci Rep. 2014;4:7162.
[3] Sleiman SF, Langley BC, Basso M, et al. Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci. 2011;31(18):6858-6870.
[4] Shen CH, Wu JY, Wang SC, et al. The suppressive role of phytochemical-induced glutathione S-transferase Mu 2 in human urothelial carcinoma cells. Biomed Pharmacother. 2022;151:113102.
[5] Duverger V, Murphy AM, Sheehan D, et al. The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF). Br J Cancer. 2004;90(10):2025-2031.
[6] Choi ES, Nam JS, Jung JY, Cho NP, Cho SD. Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer. Sci Rep. 2014;4:7162.
[7] Wei C, Zhang W, Zhou Q, et al. Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease. Neurochem Res. 2016;41(8):1924-1938.
Mithramycin A是一种从S. grieseus中分离出来的抗生素 [1]。作为特异性蛋白1（Sp1）的选择性抑制剂，Mithramycin A与富含GC的DNA序列结合，取代与癌基因启动子结合的Sp1转录因子，抑制基因表达 [2]。Mithramycin A具有抗肿瘤和神经保护作用 [3]。
在体外，Mithramycin A（0-400nM, 24h）能够剂量依赖性地抑制BFTC 905和5637细胞中GSTM2蛋白的表达 [4]。Mithramycin A（75μM; 24h）显著增加TNF诱导TF-1细胞的细胞凋亡，Mithramycin A对TNF细胞毒性的增强效应发生在FADD水平上或者在其下游位置 [5]。
在体内，Mithramycin A（0.2mg/kg/day; three times per week for 29 days; i.p.）显著降低人类宫颈癌细胞异种移植小鼠的肿瘤体积，并且增加了肿瘤异种移植物中的TUNEL阳性细胞数量[6]。Mithramycin A（150μg/kg/day; 60 days; i.p.）治疗能够有效抑制APPswe/PS1dE9小鼠的Sp1激活水平，显著降低小鼠大脑Aβ水平和斑块负荷，并且减少tau过度磷酸化，增加突触标记物 [7]。