Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest.
Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest.
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DOI：
10.1021/mp3004622
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发表时间：
2013-01-07
影响因子：
4.9
通讯作者：
Labhasetwar V
中科院分区：
文献类型：
--
作者：
Vijayaraghavalu S;Dermawan JK;Cheriyath V;Labhasetwar V
表观遗传学改变，如异常DNA甲基化和组蛋白修饰，在很大程度上有助于耐药性的产生和维持。这些表观遗传变化导致参与关键DNA损伤反应途径的肿瘤抑制基因沉默，使耐药癌细胞对传统抗癌药物治疗无反应。我们的假设是，用表观遗传药物治疗耐药细胞可以通过重新激活先前沉默的基因来恢复对抗癌药物的敏感性。为了验证我们的假设，我们使用了耐药乳腺癌细胞（MCF-7/ADR）和两种通过不同机制起作用的表观遗传药物-5-氮杂-2 ′脱氧胞苷（地西他滨，DAC），一种去甲基化剂和辛二酰苯胺异羟肟酸（SAHA），一种组蛋白去乙酰化酶催化剂-与阿霉素联合使用。我们表明，耐药细胞的顺序治疗，首先用表观遗传药物（DAC），然后用阿霉素，诱导高度协同效应，从而降低阿霉素的IC 50几千倍。序贯处理导致超过90%的耐药细胞经历G2/M细胞周期停滞，确定是由于负责细胞周期调节的p21 WAF 1/CIP 1表达上调。p21 WAF 1/CIP 1的诱导与DNA甲基转移酶1（DNMT 1）的耗竭密切相关，DNMT 1是一种促进DNA甲基化的酶，这表明p21 WAF 1/CIP 1基因可能已被甲基化，因此在MCF-7/ADR细胞中无活性。微阵列分析表明，表达的几个肿瘤抑制基因和肿瘤启动子基因的下调，特别是在顺序处理的耐药细胞。序贯治疗比同步治疗更有效，DAC在克服阿霉素耐药方面比SAHA更有效。在药物敏感的乳腺癌细胞中也观察到了序贯治疗的协同效应，但这种效应在耐药细胞中更为明显。总之，表观遗传药物与多柔比星联合序贯治疗诱导了高度协同效应，克服了乳腺癌细胞中的多柔比星耐药性。
Epigenetic alterations such as aberrant DNA methylation and histone modifications contribute substantially to both the cause and maintenance of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Our hypothesis is that treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes. To test our hypothesis, we used drug-resistant breast cancer cells (MCF-7/ADR) and two epigenetic drugs that act via different mechanisms—5-aza-2′ deoxycytidine (Decitabine, DAC), a demethylating agent and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor—in combination with doxorubicin. We show that the sequential treatment of resistant cells, first with an epigenetic drug (DAC), and then with doxorubicin, induces a highly synergistic effect, thus reducing the IC50 of doxorubicin by several thousand folds. The sequential treatment caused over 90% resistant cells to undergo G2/M cell cycle arrest, determined to be due to upregulation of p21WAF1/CIP1 expression, which is responsible for cell-cycle regulation. The induction of p21WAF1/CIP1 correlated well with the depletion of DNA methyltransferase1 (DNMT1), an enzyme that promotes methylation of DNA, suggesting that the p21WAF1/CIP1 gene may have been methylated and hence is inactive in MCF-7/ADR cells. Microarray analysis shows expression of several tumor suppressor genes and downregulation of tumor promoter genes, particularly in sequentially treated resistant cells. Sequential treatment was found to be significantly more effective than simultaneous treatment, and DAC was more effective than SAHA in overcoming doxorubicin resistance. Synergistic effect with sequential treatment was also seen in drug-sensitive breast cancer cells, but the effect was significantly more pronounced in resistant cells. In conclusion, the sequential treatment of an epigenetic drug in combination with doxorubicin induces a highly synergistic effect that overcomes doxorubicin resistance in breast cancer cells.
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影响因子：
4.7
作者：
Drenzek, Jessica G.;Seiler, Nicole L.;Rose, Stephen L.
通讯作者：
Rose, Stephen L.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
8
作者：
Ijichi, H;Otsuka, M;Omata, M
通讯作者：
Omata, M
影响因子：
3.6
作者：
Kang, MR;Chung, IK
通讯作者：
Chung, IK
影响因子：
20.3
作者：
Galm, O;Yoshikawa, H;Herman, JG
通讯作者：
Herman, JG