Department of Gerontology, Federal University of São Carlos, Rodovia Washington Luís, Km 235, São Carlos, SP, 13565-905, Brazil.
E-signal Lab, Biochemistry Department, Institute of Chemistry, São Paulo University, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil.
Cell Oncol (Dordr). 2020 Oct;43(5):915-929. doi: 10.1007/s13402-020-00539-z. Epub 2020 Aug 6.
Although doxorubicin is widely used to treat cancer, severe side effects limit its clinical use. Combination of standard chemotherapy with natural products can increase the efficacy and attenuate the side effects of current therapies. Here we studied the anticancer effects of a combined regimen comprising doxorubicin and [10]-gingerol against triple-negative breast cancer, which does not respond to hormonal or targeted therapies.
Cytotoxicity was evaluated by MTT assay, cell cycle progression and apoptosis were analyzed by flow cytometry and signaling pathways were analyzed by Western blotting in human and murine triple negative breast cancer cell systems. The anticancer/antimetastatic and toxic effects of the combined regimen was evaluated using syngeneic and xenograft orthotopic models.
The combination of doxorubicin and [10]-gingerol significantly increased the number of apoptotic cells, compared to each compound alone. In 4T1Br4 cells, the combined regimen was the only condition able to increase the levels of active caspase 3 and γH2AX and to decrease the level of Cdk-6 cyclin. In vivo, doxorubicin (3 mg/Kg, D3) and [10]-gingerol (10 mg/Kg, G10) resulted in a significant reduction in the volume of primary tumors and a decrease in the number of circulating tumor cells (CTCs). Interestingly, only the combined regimen led to decreased tumor burdens to distant organs (i.e., metastasis) and reduced chemotherapy-induced weight loss and hepatotoxicity in tumor-bearing animals. Likewise, in a xenograft model, only the combined regimen was effective in significantly reducing the primary tumor volume and the prevalence of CTCs.
Our data indicate that [10]-gingerol has potential to be used as a neoadjuvant or in combined therapy with doxorubicin, to improve its anticancer activity.
尽管阿霉素被广泛用于治疗癌症，但严重的副作用限制了其临床应用。将标准化疗与天然产物相结合可以提高疗效并减轻当前疗法的副作用。在这里，我们研究了阿霉素和[10]-姜酚联合方案对三阴性乳腺癌的抗癌作用，三阴性乳腺癌对激素或靶向治疗无反应。
通过 MTT 测定法评估细胞毒性，通过流式细胞术分析细胞周期进展和细胞凋亡，通过 Western blot 分析信号通路，在人源和鼠源三阴性乳腺癌细胞系统中。通过同源和异种移植原位模型评估联合方案的抗癌/抗转移和毒性作用。
与单独使用每种化合物相比，阿霉素和[10]-姜酚的联合使用显著增加了凋亡细胞的数量。在 4T1Br4 细胞中，联合方案是唯一能够增加活性 caspase 3 和 γH2AX 水平并降低 Cdk-6 细胞周期蛋白水平的条件。在体内，阿霉素（3mg/Kg，D3）和[10]-姜酚（10mg/Kg，G10）导致原发性肿瘤体积显著缩小，循环肿瘤细胞（CTC）数量减少。有趣的是，只有联合方案导致肿瘤负荷向远处器官（即转移）降低，并减少荷瘤动物的化疗诱导体重减轻和肝毒性。同样，在异种移植模型中，只有联合方案能有效显著降低原发性肿瘤体积和 CTC 的发生率。
我们的数据表明，[10]-姜酚有可能被用作阿霉素的新辅助治疗或联合治疗，以提高其抗癌活性。
