The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
Department of Biological Science, National University of Singapore, Singapore, 117543, Singapore.
Sci Rep. 2017 Dec 18;7(1):17724. doi: 10.1038/s41598-017-16436-9.
Carboplatin, a second-generation platinum agent, has been used as a cancer therapy for decades and exhibits strong anti-tumor activity. However, the wide application of carboplatin is largely limited due to its side effects, especially myelosuppression. Here, we combined carboplatin with curcumin, a natural product that improves tumor-induced anemia, for the treatment of fibrosarcoma to improve the side effects of carboplatin. We first examined the synergistic and attenuated effects of the two agents in a T241-bearing mouse model. The combination therapy caused no obvious synergistic effect, but curcumin significantly improved the survival rate of carboplatin-treated mice. Histologic analysis of the kidney and bone marrow revealed that curcumin improved carboplatin-induced myelosuppression but did not affect the kidney. To determine the mechanism involved, we introduced a probe derived from curcumin to identify its targets in bone marrow cells and the results provided us a clue that curcumin might affect the DNA repair pathway. Western blot analysis revealed that curcumin up-regulated BRCA1, BRCA2 and ERCC1 expression in bone marrow. In conclusion, curcumin attenuates carboplatin-induced myelosuppression by activating the DNA repair pathway in bone marrow cells.
卡铂，一种第二代铂类药物，已被用作癌症治疗药物数十年，具有很强的抗肿瘤活性。然而，由于其副作用，特别是骨髓抑制，卡铂的广泛应用在很大程度上受到限制。在这里，我们将卡铂与姜黄素联合用于纤维肉瘤的治疗，以改善卡铂的副作用。姜黄素是一种天然产物，可改善肿瘤引起的贫血。我们首先在 T241 荷瘤小鼠模型中检查了这两种药物的协同和减弱作用。联合治疗没有明显的协同作用，但姜黄素显著提高了卡铂治疗小鼠的存活率。对肾脏和骨髓的组织学分析表明，姜黄素改善了卡铂引起的骨髓抑制，但对肾脏没有影响。为了确定所涉及的机制，我们引入了一种源自姜黄素的探针来鉴定其在骨髓细胞中的靶标，结果为我们提供了一个线索，即姜黄素可能影响 DNA 修复途径。Western blot 分析显示，姜黄素上调了骨髓中 BRCA1、BRCA2 和 ERCC1 的表达。总之，姜黄素通过激活骨髓细胞中的 DNA 修复途径来减轻卡铂引起的骨髓抑制。
