Mithramycin A

Mithramycin AはS. grieseusから分離された抗生物質である^[1]。特異性のタンパク質1 (Sp1)の選択的な阻害剤として、Mithramycin Aは、GCに富むDNA配列と結合し、発癌遺伝子と結合するSp1転写因子を替え、よって遺伝子の発見を阻害した^[2]。Mithramycin Aは抗腫瘍と神経保護作用を持つ^[3]。

体外で、Mithramycin A (0-400nM、24時間)はBFTC 905と5637細胞で、GSTM2タンパク質の発見を用量依存的に阻害できる^[4]。Mithramycin A (75μM；24時間)は、TNF誘発のTF-1細胞のアポトーシスを著しく増やし、TNFに対するMithramycin Aの細胞毒性の増強は、FADDレベルまたはその下流位置で起こる^[5]。

体内で、Mithramycin A (0.2mg/kg/日；29日間、週に三回；腹腔内注射)はヒト子宮頸癌細胞異種移植マウスの腫瘍体積を著しく減らし、腫瘍異種移植で、TUNEL陽性細胞の数を増やす^[6]。Mithramycin A (150μg/kg/日；60日間；腹腔内注射)の処理は、APPswe/PS1dE9マウスで、Sp1活性化レベルを効果的に阻害し、マウスの脳で、Aβレベルとプラーク負荷を著しく減らし、tauの過リン酸化を減らし、シナプスマーカーを増やす^[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.