Melichar Bohuslav, Konopleva Marina, Hu Wei, Melicharova Karolina, Andreeff Michael, Freedman Ralph S
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Gynecol Oncol. 2004 Apr;93(1):149-54. doi: 10.1016/j.ygyno.2004.01.008.
Despite the advent of new chemotherapeutic drugs in recent decades, epithelial ovarian carcinoma (EOC) remains the leading cause of death from gynecologic cancers, and new therapeutic targets and agents are urgently needed. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid with anti-tumor activity against a wide range of tumors in vitro and in vivo. CDDO is a ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of the present study was to evaluate CDDO activity in EOC cell lines in vitro.
The expression of PPARgamma was examined by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in eight EOC cell lines (2774, SKOV3, CAOV3, OVCAR3, NMP-1, HEY, 2008 and 2008.C13), and the growth inhibitory activity of CDDO was assessed using the MTT assay.
PPARgamma RNA was expressed in all eight cell lines examined, but the expression varied widely among cell lines. In contrast, CDDO showed a similar degree of activity in different EOC cell lines independent of cisplatin sensitivity, with 50% inhibitory concentrations ranging from 1 to 4 microM. Experiments combining CDDO with cisplatin and paclitaxel indicated weak antagonism. The growth-inhibitory activity of CDDO was unaffected by PPARgamma antagonist T007.
Although differences were observed in PPARgamma expression in EOC cell lines, CDDO had similar growth-inhibitory activity in all cell lines examined, indicating that the antitumor activity of CDDO in vitro is mediated by a mechanism independent of PPARgamma. The activity of CDDO in platinum-resistant cell lines is encouraging with respect to the potential clinical use of the drug.
尽管近几十年来出现了新的化疗药物，但上皮性卵巢癌（EOC）仍是妇科癌症死亡的主要原因，迫切需要新的治疗靶点和药物。2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸（CDDO）是一种新型合成三萜类化合物，在体外和体内对多种肿瘤具有抗肿瘤活性。CDDO是过氧化物酶体增殖物激活受体γ（PPARγ）的配体。本研究的目的是评估CDDO在EOC细胞系中的体外活性。
通过实时定量逆转录聚合酶链反应（RT-PCR）检测8种EOC细胞系（2774、SKOV3、CAOV3、OVCAR3、NMP-1、HEY、2008和2008.C13）中PPARγ的表达，并使用MTT法评估CDDO的生长抑制活性。
在所检测的所有8种细胞系中均表达了PPARγ RNA，但细胞系间表达差异很大。相比之下，CDDO在不同的EOC细胞系中表现出相似程度的活性，与顺铂敏感性无关，半数抑制浓度范围为1至4μM。CDDO与顺铂和紫杉醇联合实验表明存在弱拮抗作用。CDDO的生长抑制活性不受PPARγ拮抗剂T007的影响。
尽管在EOC细胞系中观察到PPARγ表达存在差异，但CDDO在所有检测的细胞系中均具有相似的生长抑制活性，表明CDDO在体外的抗肿瘤活性是由独立于PPARγ的机制介导的。CDDO在铂耐药细胞系中的活性对于该药物的潜在临床应用而言令人鼓舞。
