Arafa El-Shaimaa A, Zhu Qianzheng, Barakat Bassant M, Wani Gulzar, Zhao Qun, El-Mahdy Mohamed A, Wani Altaf A
Division of Radiobiology, Department of Radiology, The Ohio State University, Columbus, Ohio 43210, USA.
Cancer Res. 2009 Dec 1;69(23):8910-7. doi: 10.1158/0008-5472.CAN-09-1543. Epub 2009 Nov 10.
Combination of innocuous dietary components with anticancer drugs is an emerging new strategy for cancer chemotherapy to increase antitumor responses. Tangeretin is a citrus flavonoid known to inhibit cancer cell proliferation. Here, we show an enhanced response of A2780/CP70 and 2008/C13 cisplatin-resistant human ovarian cancer cells to various combination treatments of cisplatin and tangeretin. Pretreatment of cells with tangeretin before cisplatin treatment synergistically inhibited cancer cell proliferation. This combination was effective in activating apoptosis via caspase cascade as well as arresting cell cycle at G(2)-M phase. Moreover, phospho-Akt and its downstream substrates, e.g., NF-kappaB, phospho-GSK-3beta, and phospho-BAD, were downregulated upon tangeretin-cisplatin treatment. The tangeretin-cisplatin-induced apoptosis in A2780/CP70 cells was increased by phosphoinositide-3 kinase (PI3K) inhibition and siRNA-mediated Akt silencing, but reduced by overexpression of constitutively activated Akt and GSK-3beta inhibition. The overall results indicated that tangeretin exposure preconditions cisplatin-resistant human ovarian cancer cells for a conventional response to low-dose cisplatin-induced cell death occurring through downregulation of PI3K/Akt signaling pathway. Thus, effectiveness of tangeretin combinations, as a promising modality in the treatment of resistant cancers, warrants systematic clinical studies.
将无害的饮食成分与抗癌药物联合使用是癌症化疗中一种新兴的新策略，旨在增强抗肿瘤反应。橘皮素是一种已知能抑制癌细胞增殖的柑橘类黄酮。在此，我们展示了A2780/CP70和2008/C13顺铂耐药的人卵巢癌细胞对顺铂和橘皮素的各种联合治疗有增强的反应。在顺铂治疗前用橘皮素预处理细胞可协同抑制癌细胞增殖。这种联合在通过半胱天冬酶级联激活凋亡以及使细胞周期停滞在G(2)-M期方面是有效的。此外，在橘皮素-顺铂治疗后，磷酸化Akt及其下游底物，如NF-κB、磷酸化GSK-3β和磷酸化BAD均下调。抑制磷酸肌醇-3激酶（PI3K）和siRNA介导的Akt沉默可增加橘皮素-顺铂诱导的A2780/CP70细胞凋亡，但组成型激活Akt的过表达和GSK-3β抑制可降低其凋亡。总体结果表明，橘皮素预处理使顺铂耐药的人卵巢癌细胞对低剂量顺铂诱导的细胞死亡产生常规反应，这是通过下调PI3K/Akt信号通路实现的。因此，橘皮素联合治疗作为一种有前景的耐药癌症治疗方式的有效性值得进行系统的临床研究。
