Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100050, China; Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100050, China.
J Trace Elem Med Biol. 2019 Dec;56:131-138. doi: 10.1016/j.jtemb.2019.07.008. Epub 2019 Aug 19.
Cisplatin (CDDP) resistance remains a major obstacle for treatment of ovarian cancer. Iron contributes to the growth and reproduction of malignant cells, thus iron chalators can inhibit the growth of tumor cells by depleting the intracellular iron pool. The iron chelator, desferrioxamine (DFO), has performed anticancer in previous study. The aim of our study is to determine the correlation between iron-deprivation and tumor chemosensitivity in ovarian cancer.
To investigate the prognostic value of ferritin light (FTL), ferroportin (FPN), hepcidin (HAMP) and divalent metal-ion transporter-1 (DMT1) in ovarian cancer, the Kaplan-Meier analysis and the Gene Expression Profiling Interactive Analysis (GEPIA) were used. The ovarian cancer cell lines (SKOV-3 and OVCAR-3) were exposed to a gradient concentration of DFO (10, 20, 50, 100, 200 μM) and CDDP (1, 5, 10, 50,100 μM) for 24 h. The protein expression of FTL was tested. The expression of cancer stem cell (CSC) markers, including Sox2, Nanog and C-myc, were downregulated with treatment of DFO. Also, the mamosphere formation and the plation of CD44/CD133 and Aldehyde dehydrogenase (ALDH) SKOV-3 cells were reduced after treatment for 7d. Furthermore, we detected the expression of p53, BCL-2, BAX, and caspase-8.
The survival analysis revealed that high expression of FTL, DMT1, HAMP, showed poor overall survival (OS) in ovarian cancer patients. Our combined data found that DFO could effectively inhibit CSCs, improve the resistance to chemotherapy, and significantly enhanced the efficacy of CDDP therapy in vitro in promoting apoptosis. Besides, targeting molecular targets, including BAX, BCL-2, p53 and caspase-8 could serve as the clinical biomarkers to evaluate the effects of ovarian cancer. It is reasonable to believe that DFO adjuvant therapy in combination with CDDP chemotherapy can promote the improvement of treatment response in ovarian cancer patients.
Our research suggests the experimental evidence for DFO and CDDP as a new effective combination therapy to enhance the efficacy of chemical therapy in ovarian cancer.
顺铂（CDDP）耐药仍是卵巢癌治疗的主要障碍。铁有助于恶性细胞的生长和繁殖，因此铁螯合剂可以通过耗尽细胞内铁池来抑制肿瘤细胞的生长。铁螯合剂去铁胺（DFO）在先前的研究中已表现出抗癌作用。本研究旨在确定铁剥夺与卵巢癌肿瘤化疗敏感性之间的相关性。
为了研究铁蛋白轻链（FTL）、亚铁转运蛋白（FPN）、hepcidin（HAMP）和二价金属离子转运蛋白-1（DMT1）在卵巢癌中的预后价值，使用 Kaplan-Meier 分析和基因表达谱交互分析（GEPIA）。将卵巢癌细胞系（SKOV-3 和 OVCAR-3）暴露于梯度浓度的 DFO（10、20、50、100、200μM）和 CDDP（1、5、10、50、100μM）24 小时。检测 FTL 蛋白的表达。用 DFO 处理后，下调癌症干细胞（CSC）标志物 Sox2、Nanog 和 C-myc 的表达。此外，处理 7d 后，SKOV-3 细胞的mamosphere 形成和 CD44/CD133 和醛脱氢酶（ALDH）的集落形成减少。进一步检测了 p53、BCL-2、BAX 和 caspase-8 的表达。
生存分析显示，FTL、DMT1、HAMP 高表达的卵巢癌患者总体生存（OS）较差。我们的综合数据表明，DFO 能有效抑制 CSCs，提高化疗耐药性，并显著增强 CDDP 治疗体外促进凋亡的作用。此外，靶向分子靶点，包括 BAX、BCL-2、p53 和 caspase-8，可作为评估卵巢癌疗效的临床生物标志物。有理由相信，DFO 辅助治疗联合 CDDP 化疗可促进卵巢癌患者治疗反应的改善。
本研究为 DFO 和 CDDP 作为增强卵巢癌化疗疗效的新有效联合治疗提供了实验依据。
