Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.
Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.
复制标题
DOI：
10.1158/1535-7163.mct-07-2282
复制
发表时间：
2008-07
影响因子：
5.7
通讯作者：
Resar LM
中科院分区：
文献类型：
--
作者：
Di Cello F;Hillion J;Kowalski J;Ronnett BM;Aderinto A;Huso DL;Resar LM
Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We previously showed that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpressed in human leiomyosarcomas, a highly malignant uterine cancer. While epidemiologic studies indicate that individuals who take cyclooxygenase inhibitors have a lower incidence of some tumors, these inhibitors have not been evaluated in uterine cancer. Here, we show that HMGA1a mice on sulindac (a COX-1/COX-2 inhibitor) have significantly smaller uterine tumors than controls. To determine if cyclooxygenase inhibitors are active in human uterine cancers that overexpress HMGA1a, we treated cultured cells with sulindac sulfide or celecoxib (a specific COX-2 inhibitor). Both drugs block anchorage-independent growth in high-grade human uterine cancer cells that overexpress HMGA1a (MES-SA cells). In contrast, neither inhibitor blocked transformation in cells that do not overexpress HMGA1a. Moreover, xenograft tumors from MES-SA cells were significantly inhibited in mice on sulindac. More strikingly, no tumors formed in mice on celecoxib. These preclinical studies suggest that cyclooxygenase inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway. Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced stage uterine cancers.
