Temsirolimus (CCI-779)

Temsirolimus (CCI-779), an ester of rapamycin, inhibits the activity of mTOR kinase activity with an IC₅₀ value of 1.76 ± 0.15μM^[1]. Temsirolimus forms a complex with FKBP-12 (an immunophilin member of the FK506 binding protein family) to inhibit the transcription and translation functions regulated by mTOR, and can effectively inhibit the phosphorylation of mTOR substrates S6K1 and 4E-BP1^[2]. Temsirolimus has been widely used in cell and mouse models as an anti-cancer agent to induce apoptosis of cancer cells^[3].

In vitro, Temsirolimus treatment for 48h inhibited cell proliferation of A549, H1299, and H358 cells with IC₅₀ values of 0.76, 0.75, and 0.64nM, respectively^[4]. Temsirolimus treatment for 48 hours suppressed the proliferation of Bel-7402 cells with an IC₅₀ value of 8.62μM and caused G1/S phase arrest as well as cell morphology disruption^[5]. Treatment with 20μM Temsirolimus for 48 hours significantly inhibited ACC-M cells and induced the formation of autophagosomes, accompanied by an increase in the expression of autophagy-related proteins^[6].

In vivo, Temsirolimus treatment via intraperitoneal injection at 20mg/kg every 3 days for 30 days inhibited tumor volume in mice bearing RH-30 xenografts, and decreased microvessel density of tumor tissues^[7]. In the subcutaneous xenograft model of liver cancer in mice, continuous intraperitoneal injection of Temsirolimus (10mg/kg/day) for 10 days inhibited tumor growth and led to a decrease in the level of p-p70S6K in the tumor tissues^[8].

References:
[1] Shor B, Zhang W G, Toral-Barza L, et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis[J]. Cancer research, 2008, 68(8): 2934-2943.
[2] Peralba J M, DeGraffenried L, Friedrichs W, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients[J]. Clinical cancer research, 2003, 9(8): 2887-2892.
[3] Teachey D T, Obzut D A, Cooperman J, et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL[J]. Blood, 2006, 107(3): 1149-1155.
[4] Ohara T, Takaoka M, Toyooka S, et al. Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non‐small‐cell lung cancer cells[J]. Cancer science, 2011, 102(7): 1344-1349.
[5] Li S, Liang Y, Wu M, et al. The novel mTOR inhibitor CCI-779 (temsirolimus) induces antiproliferative effects through inhibition of mTOR in Bel-7402 liver cancer cells[J]. Cancer cell international, 2013, 13(1): 30.
[6] Liu W, Huang S, Chen Z, et al. Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: in vitro and in vivo[J]. Pathology-Research and Practice, 2014, 210(11): 764-769.
[7] Wan X, Shen N, Mendoza A, et al. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1α/VEGF signaling[J]. Neoplasia, 2006, 8(5): 394-401.
[8] Hui I C F, Tung E K K, Sze K M F, et al. Rapamycin and CCI‐779 inhibit the mammalian target of rapamycin signalling in hepatocellular carcinoma[J]. Liver International, 2010, 30(1): 65-75.

Temsirolimus (CCI-779)是雷帕霉素的酯类衍生物，可抑制mTOR激酶活性，IC₅₀值为1.76 ± 0.15μM^[1]。Temsirolimus通过与FKBP-12（FK506结合蛋白家族的免疫亲和素成员）形成复合物，抑制mTOR调控的转录和翻译功能，并能有效抑制mTOR底物S6K1和4E-BP1的磷酸化^[2]。Temsirolimus作为抗癌剂广泛应用于细胞和小鼠模型，可诱导癌细胞凋亡^[3]。

在体外，Temsirolimus处理48小时可抑制A549、H1299和H358细胞增殖，IC₅₀值分别为0.76nM、0.75nM和0.64nM^[4]。Temsirolimus处理48小时抑制Bel-7402细胞增殖，IC₅₀值为8.62μM，并可导致G1/S期阻滞和细胞形态破坏^[5]。20μM的Temsirolimus处理ACC-M细胞48小时能显著抑制细胞增殖并诱导自噬体形成，同时增加自噬相关蛋白表达^[6]。

在体内，RH-30异种移植瘤小鼠每3天腹腔注射Temsirolimus（20mg/kg；持续30天）可抑制肿瘤体积并降低肿瘤组织微血管密度^[7]。肝癌皮下异种移植瘤小鼠模型连续腹腔注射Temsirolimus（10mg/kg/day；持续10天）能抑制肿瘤生长，并降低肿瘤组织中p-p70S6K水平^[8]。