Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico.
Am J Pathol. 2018 Feb;188(2):515-524. doi: 10.1016/j.ajpath.2017.10.018. Epub 2017 Nov 21.
Epidemiologic studies report improved breast cancer survival in women who receive ketorolac (Toradol) for postoperative pain relief compared with other analgesic agents. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. The goal of this study was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor virus-polyoma middle T-antigen model. Mice were administered ketorolac orally at 1 mg/kg twice daily to approximate the typical human dose. Mammary glands were analyzed for tumor number and immunohistochemical markers of proliferation and differentiation. R-ketorolac treatment significantly reduced mammary epithelial proliferation, based on Ki67 staining, and suppressed tumor development. Proliferative mammary epithelium from R-ketorolac-treated mice displayed greater differentiation, based on significantly higher total E-cadherin and decreased keratin 5 staining than epithelium of placebo-treated mice. No differences were detected in estrogen receptor, progesterone receptor, β-catenin, or vimentin expression between placebo and R-ketorolac treatment groups. These findings indicate that R-ketorolac treatment slows tumor progression in an aggressive model of breast cancer. R-ketorolac may thus represent a novel therapeutic approach for breast cancer prevention or treatment based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor.
流行病学研究报告称，与其他镇痛剂相比，接受酮咯酸（Toradol）用于术后疼痛缓解的女性乳腺癌生存率有所提高。酮咯酸是一种外消旋药物。S-对映体抑制环氧化酶；R-酮咯酸是 Ras 相关 C3 肉毒梭菌毒素底物 1（Rac1）和细胞分裂控制蛋白 42（Cdc42）的选择性抑制剂，这些信号分子在乳腺癌进展和转移过程中上调。本研究的目的是确定 R-酮咯酸是否会改变鼠乳腺肿瘤病毒-多瘤病毒中 T 抗原模型中的乳腺癌发展。每天两次以 1mg/kg 的剂量给小鼠口服酮咯酸，近似于典型的人类剂量。分析乳腺的肿瘤数量和增殖和分化的免疫组织化学标志物。基于 Ki67 染色，R-酮咯酸治疗显著降低了乳腺上皮细胞的增殖，并抑制了肿瘤的发展。与安慰剂治疗的小鼠相比，R-酮咯酸治疗的增殖性乳腺上皮细胞显示出更高的分化，总 E-钙黏蛋白显著增加，角蛋白 5 染色减少。在安慰剂和 R-酮咯酸治疗组之间，雌激素受体、孕激素受体、β-连环蛋白或波形蛋白的表达没有差异。这些发现表明，R-酮咯酸治疗可减缓侵袭性乳腺癌模型中的肿瘤进展。因此，R-酮咯酸可能因其作为 Rac1 和 Cdc42 抑制剂的药理活性而成为预防或治疗乳腺癌的新治疗方法。
