Plitidepsin is a cyclic depsipeptide that targets eEF1A2, with a KD value of 80nM [1]. Plitidepsin inhibits the replication of SARS-CoV-2 by suppressing the activity of eEF1A, with an IC50 value of 0.73nM[2]. Plitidepsin can induce a dose-dependent cell cycle arrest process, accompanied by the induction of early oxidative stress, the rapid activation of Rac1 GTPase, and the continuous activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK), ultimately leading to caspase-dependent apoptosis[3]. Plitidepsin has been widely used to inhibit the growth of various cancer cells and xenograft tumors[4].
In vitro, Plitidepsin treatment for 48 hours significantly inhibited the proliferation of KOC-7C cells, RMG-I cells, and TOV-21G cells, with IC50 values of 3.61nM, 4.97nM, and 2.51nM, respectively[5]. Treatment with 450nM Plitidepsin for 6 hours induced endoplasmic reticulum stress and autophagy in HeLa cells and promoted the degradation of the CHOP protein[6].
In vivo, Plitidepsin treatment via intraperitoneal injection at a dose of 90μg/kg five times a week for 1 week significantly inhibited the serum paraprotein concentration and myeloma-related angiogenesis in the 5T33MMvv myeloma mouse model [7]. For three consecutive days, a daily intraperitoneal injection of 1mg/kg dose of Plitidepsin was administered, which significantly inhibited tumor growth in the ARO-81 cell-xenograft mouse model, and suppressed the expression of multiple angiogenesis genes[8].
References:
[1] Losada A, Muñoz-Alonso M J, García C, et al. Translation elongation factor eEF1A2 is a novel anticancer target for the marine natural product plitidepsin[J]. Scientific reports, 2016, 6(1): 35100.
[2] White K M, Rosales R, Yildiz S, et al. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A[J]. Science, 2021, 371(6532): 926-931.
[3] Alonso-Álvarez S, Pardal E, Sánchez-Nieto D, et al. Plitidepsin: design, development, and potential place in therapy[J]. Drug Design, Development and Therapy, 2017: 253-264.
[4] Barboza N M, Medina D J, Budak-Alpdogan T, et al. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab[J]. Cancer biology & therapy, 2012, 13(2): 114-122.
[5] Miyake R, Yamanaka S, Matsubara S, et al. Preclinical activity of plitidepsin against clear cell carcinoma of the ovary[J]. Anticancer Research, 2021, 41(9): 4277-4285.
[6] Losada A, Berlanga J J, Molina-Guijarro J M, et al. Generation of endoplasmic reticulum stress and inhibition of autophagy by plitidepsin induces proteotoxic apoptosis in cancer cells[J]. Biochemical pharmacology, 2020, 172: 113744.
[7] Caers J, Menu E, De Raeve H, et al. Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma[J]. British journal of cancer, 2008, 98(12): 1966-1974.
[8] Straight A M, Oakley K, Moores R, et al. Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes[J]. Cancer chemotherapy and pharmacology, 2006, 57(1): 7-14.
Plitidepsin是一种环状缩肽，靶向eEF1A2，KD值为80nM[1]。Plitidepsin通过抑制eEF1A的活性来抑制 SARS-CoV-2的复制，IC50值为0.73nM[2]。Plitidepsin可诱导剂量依赖性的细胞周期阻滞过程，同时伴有早期氧化应激的诱导、Rac1 GTPase的快速激活以及c-Jun N-terminal kinase (JNK)和p38丝裂原活化蛋白激酶的持续激活，最终导致caspase依赖性凋亡[3]。Plitidepsin已被广泛用于抑制多种癌细胞和异种移植肿瘤的生长[4]。
在体外，Plitidepsin处理48小时显著抑制了KOC-7C细胞、RMG-I细胞和TOV-21G细胞的增殖，IC50值分别为3.61nM、4.97nM和2.51nM[5]。使用450nM的Plitidepsin处理HeLa细胞6小时，诱导了内质网应激和自噬，并促进了CHOP蛋白的降解[6]。
在体内，每周五次腹腔注射90µg/kg剂量的Plitidepsin，持续1周，显著抑制了5T33MMvv骨髓瘤小鼠模型中的血清paraprotein浓度和骨髓瘤相关的血管生成[7]。连续三天每日腹腔注射1mg/kg剂量的Plitidepsin，显著抑制了ARO-81细胞异种移植小鼠模型中的肿瘤生长，并抑制了多种血管生成基因的表达[8]。