Samy Ramar Perumal, Gopalakrishnakone Ponnampalam, Ignacimuthu Savarimuthu
Venom and Toxin Research Programme, Department of Anatomy, Yong Loo Lin School of Medicine, MD 10, 4 Medical Drive, National University of Singapore, Singapore 117597.
Chem Biol Interact. 2006 Dec 1;164(1-2):1-14. doi: 10.1016/j.cbi.2006.08.018. Epub 2006 Aug 30.
In this study, we evaluated the anti-tumor potential of luteolin (30mg/kg, p.o.), combined with cyclophosphamide (10mg/kg, i.p.) (LU+CYC) orally administered for 20 days; and CYC individually for 10 days against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in Wistar rats. Combination treatment (LU+CYC) inhibited the incidence rate of tumors and decreased tumor volume significantly without changing the total body weight of the animals. Long-term treatment did not show any apparent toxicity in rats. The CYC-treated group showed potential reduction of tumor volume (74%), severe toxicity, and loss of body weight. In order to elucidate the anticancer mechanism of luteolin, antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) generation in the liver, kidney and breast, as well as protein profiles, were also examined. Biochemical analysis of the combination-treated group showed significant (P<0.01; P<0.05) inhibition of lipid peroxide (LPx) formation (oxygen-free radicals), the level and the activity of SOD, CAT and GPx were found to be very high than the LU and CYC individually treated rats at a 30mg/kg dose. 2D gel electrophoresis analysis revealed that (56kDa) high molecular weight protein was detected in tumors of rats receiving combination treatment than the cancer controls. The biological significance of that protein involved for the dysfunction of cancer cells and induces apoptosis. Histopathological changes also confirmed the formation of tumor tubules and neovascularization after the treatment. Overall, these results suggest that the combination treatment provided antioxidant defense with strong chemopreventive activity against the genesis of DMBA-induced mammary tumors.
在本研究中，我们评估了木犀草素（30mg/kg，口服）联合环磷酰胺（10mg/kg，腹腔注射）（LU+CYC）口服给药20天；以及单独使用环磷酰胺给药10天对7,12-二甲基苯并(a)蒽（DMBA）诱导的Wistar大鼠乳腺癌变的抗肿瘤潜力。联合治疗（LU+CYC）显著抑制了肿瘤发生率并减小了肿瘤体积，且未改变动物的总体重。长期治疗未在大鼠中显示出任何明显毒性。环磷酰胺治疗组显示出肿瘤体积有潜在减小（74%）、严重毒性和体重减轻。为了阐明木犀草素的抗癌机制，还检测了肝脏、肾脏和乳腺中的超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）等抗氧化活性以及蛋白质谱。联合治疗组的生化分析显示脂质过氧化物（LPx）形成（氧自由基）受到显著抑制（P<0.01；P<0.05），在剂量为30mg/kg时，SOD、CAT和GPx的水平和活性比单独接受木犀草素和环磷酰胺治疗的大鼠高得多。二维凝胶电泳分析显示，与癌症对照组相比，接受联合治疗的大鼠肿瘤中检测到（56kDa）高分子量蛋白质。该蛋白质的生物学意义涉及癌细胞功能障碍并诱导细胞凋亡。组织病理学变化也证实了治疗后肿瘤小管和新血管形成。总体而言，这些结果表明联合治疗提供了抗氧化防御，对DMBA诱导的乳腺肿瘤发生具有强大的化学预防活性。
