Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats.
Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats.
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DOI：
10.1186/1471-2407-9-107
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发表时间：
2009-04-08
期刊：
影响因子：
3.8
通讯作者：
Gupta J
中科院分区：
文献类型：
--
作者：
Tikoo K;Kumar P;Gupta J
抗塑性药物顺铂仍然是包括乳腺癌在内的各种实体肿瘤的选择，但依赖性的肾毒性是大多数基于铂的化学疗法的主要缺点进行研究是为了评估Rosiglitazone（PPARγ激动剂和抗炎剂）对顺铂诱导的肾毒性及其在DMBA诱导的乳腺癌大鼠中的抗癌活性的影响。
通过口服二甲基苯甲酸[a]蒽（DMBA）（60 mg/kg），在雌性sprague-dawley大鼠中诱导了乳腺肿瘤。通过蛋白质印迹检查H3，有丝分裂原激活的蛋白（MAP）激酶p38表达和PPAR-γ表达。
我们的数据表明，TNF-α参与了顺铂诱导的肾毒性，罗斯列唑酮与顺铂的预处理会增加乳腺肿瘤的p38，PPAR-γ的表达，并显示出最大的肿瘤范围。乳腺肿瘤中组蛋白H3的甲基化通过罗格列酮的预处理来改善。
据我们所知，这是第一份报告表明，罗格列酮的预处理使顺铂的抗癌活性协同，并最大程度地减少顺铂诱导的DMBA诱导乳腺癌的肾毒性。
Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. But dose dependent nephrotoxicity is the major drawback in majority of platinum based chemotherapy regimens. Recent reports have shown that inflammatory pathways are the main offender for cisplatin induced nephrotoxicity. The present study was undertaken to assess the effect of rosiglitazone, a PPARγ agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats. Mammary tumours were induced in female Sprague-Dawley rats by feeding orally with dimethylbenz [a]anthracene (DMBA) (60 mg/kg). Cisplatin induced nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Posttranslational modifications of histone H3, mitogen-activated protein (MAP) kinase p38 expression and PPAR-γ expression were examined by western blotting. Our data shows involvement of TNF-α in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-γ in mammary tumours and shows maximum tumour reduction. Furthermore, cisplatin induced changes in histone acetylation, phosphorylation and methylation of histone H3 in mammary tumours was ameliorated by pre-treatment of rosiglitazone. Suggesting, PPAR-γ directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications. To best of our knowledge this is the first report which shows that pre-treatment of rosiglitazone synergizes the anticancer activity of cisplatin and minimizes cisplatin induced nephrotoxicity in DMBA induced breast cancer.
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