Salinosporamide A (NPI-0052, Marizomib)

Salinosporamide A (NPI-0052, Marizomib) is a 20S proteasome inhibitor isolated from the obligate marine actinobacterium Salinispora tropica, exhibiting potent antitumor activity with an IC₅₀ value of 1.3nM^[1,2]. The 20S proteasome is an enzyme complex responsible for intracellular protein degradation, playing a crucial role in maintaining cellular proteostasis, including the clearance of abnormal proteins and the regulation of the cell cycle^[3]. Salinosporamide A is commonly used in the treatment and research of glioblastoma and neurodegenerative diseases^[4].

In vitro, treatment of Jurkat T cells with Salinosporamide A (10nM) for 24h significantly arrested the cell cycle at the G2/M phase and downregulated the expression of cyclinA and cyclinD1^[5]. Pretreatment of human lung adenocarcinoma H1299 cells with Salinosporamide A (50nM) for 4h, followed by stimulation with 1nM tumor necrosis factor α (TNF) for 24h, inhibited TNF-induced tumor cell invasion. Pretreatment of mouse macrophage RAW 264.7 cells with Salinosporamide A (50nM) for 4h, followed by stimulation with 5nM receptor activator of nuclear factor κB ligand (RANKL) for 5 days, suppressed RANKL-induced osteoclastogenesis and differentiation^[6].

In vivo, co-administration of Salinosporamide A (0.025mg/kg) with bortezomib (0.25mg/kg) via intraperitoneal injection twice weekly for 28 days in nude mice bearing pheochromocytoma (MTT-Luc) xenografts significantly reduced tumor cell proliferation and angiogenesis, while increasing apoptotic cell death^[7]. In a Plasmodium yoelii-infected Swiss-Webster mouse model, subcutaneous injection of Salinosporamide A (130μg/kg) on days 1, 2, and 4 post-infection effectively inhibited active parasite replication and nearly cleared parasitemia^[8].

References:
[1] FELING R H, BUCHANAN G O, MINCER T J, et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora[J]. Angewandte Chemie International Edition, 2003, 42(3): 355-357.
[2] FENICAL W, JENSEN P R, PALLADINO M A, et al. Discovery and development of the anticancer agent salinosporamide A (NPI-0052)[J]. Bioorganic & Medicinal Chemistry, 2009, 17(6): 2175-2180.
[3] DESHMUKH S K, YAFFE D, OLSHINA M A, et al. The contribution of the 20S proteasome to proteostasis[J]. Biomolecules, 2019, 9(5): 190.
[4] MIR R H, MIR P A, UPPAL J, et al. Evolution of natural product scaffolds as potential proteasome inhibitors in developing cancer therapeutics[J]. Metabolites, 2023, 13(4): 509.
[5] LEE H S, JEONG G S. Salinosporamide A, a marine-derived proteasome inhibitor, inhibits T cell activation through regulating proliferation and the cell cycle[J]. Molecules, 2020, 25(21): 5031.
[6] AHN K S, SETHI G, CHAO T H, et al. Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-κB–regulated gene products[J]. Blood, 2007, 110(7): 2286-2295.
[7] BULLOVA P, COUGNOUX A, MARZOUCA G, et al. Bortezomib alone and in combination with salinosporamid A induces apoptosis and promotes pheochromocytoma cell death in vitro and in female nude mice[J]. Endocrinology, 2017, 158(10): 3097-3108.
[8] PRUDHOMME J, MCDANIEL E, PONTS N, et al. Marine actinomycetes: a new source of compounds against the human malaria parasite[J]. PLoS One, 2008, 3(6): e2335.

Salinosporamide A (NPI-0052, Marizomib)是一种从专性海洋放线菌热带盐孢菌Salinispora tropica中分离出来的，具有强效抗肿瘤活性的20S蛋白酶体抑制剂，IC₅₀值为1.3nM^[1,2]。20S蛋白酶体是一种在细胞内负责蛋白质降解的酶，对异常蛋白质清除和细胞周期调控等细胞内蛋白质稳态的维持至关重要^[3]。Salinosporamide A通常用于胶质母细胞瘤和神经退行性疾病等的治疗和研究^[4]。

在体外，Salinosporamide A（10nM）处理Jurkat T细胞24h，显著阻断了细胞周期进入G2/M期，并下调了cyclinA和cyclinD1的表达^[5]。Salinosporamide A（50nM）预处理人肺腺癌H1299细胞4h，随后用1nM肿瘤坏死因子（TNF）刺激24h，能抑制TNF诱导的肿瘤细胞侵袭能力。Salinosporamide A（50nM）预处理小鼠巨噬RAW 264.7细胞4h，随后用5nM核因子κB受体活化因子配体（RANKL）刺激5天，能抑制RANKL诱导的破骨细胞生成和分化^[6]。

在体内，Salinosporamide A（0.025mg/kg）与bortezomib（0.25mg/kg）共同对携带嗜铬细胞瘤MTT-Luc的裸鼠进行每周两次腹腔注射，持续28天后可显著减少肿瘤细胞增殖和血管生成，并增加体内凋亡细胞死亡^[7]。Salinosporamide A（130μg/kg）于Swiss-Webster小鼠感染Plasmodium yoelii后第1,2,4天经皮下注射治疗，有效地阻止了寄生虫的活跃复制，且寄生虫血症被几乎清除^[8]。