Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers.
Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers.
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DOI：
10.1158/1535-7163.mct-11-0873
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发表时间：
2012-10
影响因子：
5.7
通讯作者：
Copland JA
中科院分区：
文献类型：
--
作者：
Cooper SJ;von Roemeling CA;Kang KH;Marlow LA;Grebe SK;Menefee ME;Tun HW;Colon-Otero G;Perez EA;Copland JA
转移性实体瘤具有侵袭性，且大多具有耐药性，导致治疗选择很少且预后不良，如透明细胞肾细胞癌 (ccRCC) 和三阴性乳腺癌 (TNBC) 所示。因此，需要确定治疗转移性疾病的新治疗方案。 ccRCC 和 TNBC 细胞系用 HDAC 抑制剂罗米地辛和甲基转移酶抑制剂地西他滨治疗，这两种表观遗传修饰药物已被 FDA 批准用于治疗各种血液恶性肿瘤。利用细胞增殖分析、流式细胞术、定量PCR和免疫印迹技术来评估该药物组合的抗肿瘤协同作用，并鉴定表观遗传沉默的肿瘤抑制基因的重新表达。用罗米地辛/地西他滨联合治疗转移性 TNBC 和 4 期 ccRCC 细胞系，可协同抑制细胞生长并诱导细胞凋亡，其水平高于单独药物治疗的水平。在联合药物治疗组中观察到肿瘤抑制基因分泌卷曲相关蛋白一 (sFRP1) 的协同重新表达。在组合药物治疗之前沉默 sFRP1 (shRNA) 表明 sFRP1 介导罗米地辛/地西他滨组合的生长抑制和细胞凋亡活性。此外，将重组 sFRP1 添加到 ccRCC 或 TNBC 细胞中，通过诱导细胞凋亡，以剂量依赖性方式抑制细胞生长，表明 sFRP1 的表观遗传沉默有助于肾癌细胞和乳腺癌细胞的存活。罗米地辛和地西他滨联合治疗耐药肿瘤是一种有前途的治疗策略。此外，重组 sFRP1 可能是治疗 sFRP1 表达受抑制的癌症的一种新策略。
Metastatic solid tumors are aggressive and mostly drug resistant leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple negative breast cancer (TNBC). Therefore the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the FDA for the treatment of various hematologic malignancies. Cell proliferation analysis, flow cytometry, quantitative PCR and immuno-blotting techniques were utilized to evaluate the antitumor synergy of this drug combination and identify the re-expression of epigenetically silenced tumor suppressor genes. Combinatorial treatment of metastatic TNBC and stage 4 ccRCC cell lines with romidepsin/decitabine leads to synergistic inhibition of cell growth and induction of apoptosis above levels of individual drug treatments alone. Synergistic re-expression of the tumor suppressor gene secreted frizzled-related protein one (sFRP1) was observed in combinatorial drug treated groups. Silencing sFRP1 (shRNA) prior to combinatorial drug treatment demonstrated that sFRP1 mediates the growth inhibitory and apoptotic activity of combined romidepsin/decitabine. Furthermore, addition of recombinant sFRP1 to ccRCC or TNBC cells inhibits cell growth in a dose-dependent manner through the induction of apoptosis identifying that epigenetic silencing of sFRP1 contributes to renal and breast cancer cell survival. Combinatorial treatment with romidepsin and decitabine in drug resistant tumors is a promising treatment strategy. Moreover, recombinant sFRP1 may be a novel therapeutic strategy for cancers with suppressed sFRP1 expression.