通过靶向和药物抑制 DNMT3b 增强高甲基化乳腺癌细胞的化疗疗效。
Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b.
机构信息
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 515 Brinkhous Bullitt Building, CB #7525, Chapel Hill, NC 27599, USA.
出版信息
Breast Cancer Res Treat. 2012 Jan;131(2):385-99. doi: 10.1007/s10549-011-1409-2. Epub 2011 Feb 27.
A subset of primary breast cancers and breast cancer cell lines express a hypermethylation defect (characterized by DNMT hyperactivity and DNMT3b overexpression) which contributes to chemotherapy resistance and provides a target for development of new treatment strategies. The objective of the current study was to determine if targeting the epigenome enhances the sensitivity of breast cancer cells to cytotoxic chemotherapy. Hypermethylator breast cancer cell lines (MDA-MB-453, BT549, and Hs578T) were treated with 250 or 500 nM 5-aza-2'-deoxycytidine (5-aza) and/or were subjected to RNAi-mediated DNMT3b knockdown (KD), and then tested for sensitivity to doxorubicin hydrochloride (DOX), paclitaxel (PAX), and 5-fluorouracil (5-FU). In MDA-MB-453 cells, DNMT3b KD reduces the IC(50) for DOX from 0.086 to 0.048 μM (44% reduction), for PAX from 0.497 to 0.376 nM (24%), and for 5-FU from 0.817 to 0.145 mM (82%). Treatment with 250 nM 5-aza for 7 days did not increase the efficacy of DOX, PAX, or 5-FU, but 7-day treatment with 500 nM 5-aza sensitized cells, reducing the IC(50) for DOX to 0.035 μM (60%), PAX to 0.311 nM (37%), and 5-FU to 0.065 mM (92%). 5-aza treatment of DNMT3b KD cells reduced the IC(50) for DOX to 0.036 μM (59%), for PAX to 0.313 nM (37%) and for 5-FU to 0.067 (92%). Similar trends of enhancement of cell kill were seen in BT549 (13-60%) and Hs578T (29-70%) cells after RNAi-mediated DNMT3b KD and/or treatment with 5-aza. The effectiveness of DOX, PAX, and 5-FU is enhanced through targeted and/or pharmacological inhibition of DNMT3b, strongly suggesting that combined epigenetic and cytotoxic treatment will improve the efficacy of breast cancer chemotherapy.
一部分原发性乳腺癌和乳腺癌细胞系表达一种超甲基化缺陷（表现为 DNMT 活性过高和 DNMT3b 过表达），这有助于化疗耐药，并为新的治疗策略的发展提供了一个靶标。本研究的目的是确定针对表观基因组是否可以提高乳腺癌细胞对细胞毒性化疗的敏感性。高甲基化乳腺癌细胞系（MDA-MB-453、BT549 和 Hs578T）用 250 或 500 nM 5-氮杂-2'-脱氧胞苷（5-aza）处理，或进行 RNAi 介导的 DNMT3b 敲低（KD），然后检测对阿霉素盐酸盐（DOX）、紫杉醇（PAX）和 5-氟尿嘧啶（5-FU）的敏感性。在 MDA-MB-453 细胞中，DNMT3b KD 将 DOX 的 IC50 从 0.086 降至 0.048 μM（降低 44%），将 PAX 的 IC50 从 0.497 降至 0.376 nM（降低 24%），将 5-FU 的 IC50 从 0.817 降至 0.145 mM（降低 82%）。用 250 nM 5-aza 处理 7 天并没有增加 DOX、PAX 或 5-FU 的疗效，但用 500 nM 5-aza 处理 7 天可使细胞敏感，将 DOX 的 IC50 降至 0.035 μM（降低 60%），PAX 的 IC50 降至 0.311 nM（降低 37%），5-FU 的 IC50 降至 0.065 mM（降低 92%）。5-aza 处理 DNMT3b KD 细胞将 DOX 的 IC50 降低至 0.036 μM（降低 59%），将 PAX 的 IC50 降低至 0.313 nM（降低 37%），将 5-FU 的 IC50 降低至 0.067（降低 92%）。在 BT549（13-60%）和 Hs578T（29-70%）细胞中，通过 RNAi 介导的 DNMT3b KD 和/或用 5-aza 处理后，也观察到细胞杀伤增强的类似趋势。通过靶向和/或药理学抑制 DNMT3b，可增强 DOX、PAX 和 5-FU 的疗效，强烈表明联合表观遗传学和细胞毒性治疗将提高乳腺癌化疗的疗效。
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