Bortezomib (PS-341)

Bortezomib (PS-341), as a dipeptide boronic acid proteasome inhibitor with antitumor activity, can potently inhibiit 20S proteasome with Ki of 0.6 nM by targeting a threonine residue[1].

In vitro, Bortezomib can retain NF-kappaB in the cytoplasm and inhibit cell growth with IC50 of 22.5 nM, in a dose/time-dependent way[2]. Bortezomib inhibited growth and induced apoptosis of PEL (primary effusion lymphomas) cell lines with IC50 values of 3.4-5.0 nM[3].

In vitro, 1 µmol/L-10 nmol/L bortezomib can activate the Akt pathway via increased SRC-3 (Steroid receptor coactivator-3)[4]. In vitro, 20 nM bortezomib induces apoptotic cell death and promotes G0/G1 phase arrest[5].

In vivo, BALB/c mice were treated with 1 mg/kg bortezomib intraperitoneally once weekly for 2 weeks increased phosphorylation of JNK (c-Jun N-terminal kinase) and extracellular signal-regulated protein kinase (ERK) in the spinal cord[6]. In vivo, mice were treated with bortezomib (2 mg/kg, i.v.) on Day1 and Day4 each week for continuous 4 weeks. bortezomib-treated mice showed enhanced mechanical hyperalgesia, decreased tail nerve conduction and sciatic nerve demyelination[7].

References:

[1] Adams J, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22.

[2] Galimberti S, et al. PS-341 (Bortezomib) inhibits proliferation and induces apoptosis of megakaryoblastic MO7-e cells. Leuk Res. 2008 Jan;32(1):103-12.

[3] An J, et al. Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia. 2004 Oct;18(10):1699-704.

[4] Ayala G, et al. Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt. Clin Cancer Res. 2008 Nov 15;14(22):7511-8.

[5] Bao X, et al. Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma. Int J Oncol. 2017 Feb;50(2):477-486.

[6] Tsubaki M., et al. Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation. Am. J. Cancer Res. 2018;8:1239-1248.

[7] Wu Z, et al. Lysosomal dysfunction in Schwann cells is involved in bortezomib-induced peripheral neurotoxicity. Arch Toxicol. 2023 May;97(5):1385-1396.

Bortezomib (PS-341) 作为一种具有抗肿瘤活性的二肽硼酸蛋白酶体抑制剂,可通过靶向苏氨酸残基,有效抑制Ki为0.6 nM的20S蛋白酶体[1]。

在体外,硼替佐米可将 NF-kappaB 保留在细胞质中,并以剂量/时间依赖性的方式抑制细胞生长(IC50=22.5 nM)[2]。硼替佐米能抑制 PEL(原发性渗出性淋巴瘤)细胞系的生长并诱导其凋亡,IC50 值为 3.4-5.0 nM[3]。

在体外,1 µmol/L-10 nmol/L 硼替佐米可通过增加 SRC-3(类固醇受体辅激活剂-3)激活 Akt 通路[4]。在体外,20 nM 硼替佐米可诱导细胞凋亡并促进 G0/G1 期停滞[5]。

在体内,BALB/c 小鼠每周一次腹腔注射 1 毫克/千克硼替佐米,连续 2 周后,脊髓中JNK(c-Jun N端激酶)和细胞外信号调节蛋白激酶(ERK)的磷酸化增加[6]。在体内,每周第1天和第4天用硼替佐米(2 mg/kg,静脉注射)治疗小鼠,连续4周。经硼替佐米处理的小鼠表现出机械性痛觉减退、尾神经传导减弱和坐骨神经脱髓鞘[7]。