Mol Can Thera：联合用药可有效治疗乳腺癌和肾透明细胞癌

近日，来自美国梅奥诊所的研究者通过研究揭示了一种强有力的治疗两种致命性癌症-三阴性乳腺癌和肾透明细胞癌（常见的肾癌）的方法。相关研究成果刊登在了国际杂志Molecular Cancer Therapeutics上，文章中，研究者报道了两种药物，罗咪酯肽和地西他滨，两种药物可以协作来激活肿瘤抑制基因抑制肿瘤发生。用药后，肿瘤抑制基因会分泌卷曲相关蛋白sFRP1，随后肿瘤细胞便会停止生长，并且死亡。

罗咪酯肽和地西他滨两种药物得到了FDA批准，用于治疗血癌和检测固体癌症。研究者Copland博士表示，我们目前临床试验的技术来证明这两种药物抗击癌症的效果。sFRP1在结肠癌、肺癌和肝癌中是无效的。研究者和其同事早期研究中发现sFRP1在特定的肿瘤中是沉默的，新的研究工作揭示了其表达可以罗咪酯肽和地西他滨恢复，罗咪酯肽是一种组蛋白脱乙酰基酶抑制剂，而地西他滨是一种甲基转移酶抑制剂。两种药物可以以特定方式修饰基因来影响其表达与否。

单独来讲，每种药物并不能又到任何形式的癌细胞死亡，但是实验室研究揭示，如果两种药物联合作用却可以杀死肾癌和三阴性乳腺癌，这两种癌症每年在美国会影响超过80，000人的健康。如今这种药物结合疗法对于癌症病人的治疗无疑是一种希望。而且研究者表示，也可通过活检技术来分辨出肿瘤患者中是否有sFRP1功能的缺失。这项研究由美国国立卫生研究院支持。

编译自：Drug Duo Turns On Cancer-Fighting Gene in Kidney, Breast Cancers

doi:10.1158/1535-7163.MCT-11-0873
PMC:
PMID:

Re-expression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers.

Simon J Cooper1, Christina A Von Roemeling2, Kylie H Kang3, Laura A Marlow2, Stefan KG Grebe4, Michael E Menefee5, Han W Tun6, Gerardo Colon-Otero7, Edith A. Perez7, and John A Copland8,*

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.