Nanogel-mediated delivery of a cocktail of epigenetic drugs plus doxorubicin overcomes drug resistance in breast cancer cells.
Nanogel-mediated delivery of a cocktail of epigenetic drugs plus doxorubicin overcomes drug resistance in breast cancer cells.
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DOI：
10.1007/s13346-018-0556-y
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发表时间：
2018-10
影响因子：
5.4
通讯作者：
Labhasetwar V
中科院分区：
文献类型：
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作者：
Vijayaraghavalu S;Labhasetwar V
表观遗传修饰（例如，DNA甲基化或组蛋白去乙酰化）通常与癌症的化学抗性有关。我们以前的研究表明，用去甲基化剂（5-氮杂-2 ′-脱氧胞苷; DAC）或组蛋白去乙酰化酶抑制剂（辛二酰苯胺异羟肟酸; SAHA）预处理耐药MCF-7/ADR乳腺癌细胞，使耐药细胞对阿霉素（DOX）治疗敏感。然而，即使随着DOX剂量的增加，一部分耐药细胞仍然对这种预处理无反应（约25%用DAC预处理，约45%用SAHA预处理）。我们假设用表观遗传药物组合（DAC + SAHA）预处理耐药细胞可以更有效地克服耐药性。我们假设，递送封装在可生物降解纳米凝胶（NG）中的表观遗传药物将进一步增强其功效。MCF-7/ADR细胞首先用单一药物与表观遗传药物的组合处理，作为溶液或包封在NG中，然后在溶液或NG中经受DOX。抗增殖数据显示，在NG中用表观遗传药物预处理，然后在NG中用DOX预处理，在克服抗性方面最有效;这种处理抑制细胞生长> 90%，即使在低剂量的DOX下。细胞周期分析显示，用表观遗传药物+ DOX的混合物处理的细胞的主要部分（全部在NG制剂中）保持在G2/M细胞周期停滞期持续较长时间。表观遗传药物治疗NGs的机制可能是其持续作用。类似的策略可以用于其他癌细胞，其中耐药性是由于表观遗传修饰。
Epigenetic modifications (e.g., DNA methylation or histone deacetylation) are commonly implicated in cancer chemoresistance. We previously showed that pretreating resistant MCF-7/ADR breast cancer cells with a demethylating agent (5-aza-2′-deoxycytidine; DAC) or with an inhibitor of histone deacetylase (suberoylanilide hydroxamic acid; SAHA) sensitized resistant cells to doxorubicin (DOX) treatment. However, even with increasing doses of DOX, a fraction of resistant cells remained nonresponsive to this pretreatment (~25% pretreated with DAC, ~45% with SAHA). We hypothesized that pretreating resistant cells with a combination of epigenetic drugs (DAC + SAHA) could more effectively overcome drug resistance. We postulated that delivery of epigenetic drugs encapsulated in biodegradable nanogels (NGs) would further enhance their efficacy. MCF-7/ADR cells were first treated with a single drug vs. a combination of epigenetic drugs, either as solutions or encapsulated in NGs, then subjected to DOX, either in solution or in NGs. Antiproliferative data showed that pretreatment with epigenetic drugs in NGs, then with DOX in NGs, was most effective in overcoming resistance; this treatment inhibited cell growth by >90%, even at low doses of DOX. Cell-cycle analysis showed that a major fraction of cells treated with a cocktail of epigenetic drugs + DOX, all in NG formulations, remained in the G2/M cell-cycle arrest phase for a prolonged period. The mechanism of better efficacy of epigenetic drugs in NGs could be attributed to their sustained effect. A similar strategy could be developed for other cancer cells in which drug resistance is due to epigenetic modifications.
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影响因子：
3.7
作者：
Boettcher, Michael;Kischkel, Frank;Hoheisel, Joerg D.
通讯作者：
Hoheisel, Joerg D.
影响因子：
4.9
作者：
Vijayaraghavalu S;Dermawan JK;Cheriyath V;Labhasetwar V
通讯作者：
Labhasetwar V
影响因子：
4.9
作者：
Vijayaraghavalu S;Peetla C;Lu S;Labhasetwar V
通讯作者：
Labhasetwar V
影响因子：
9.7
作者：
Vijayaraghavalu, Sivakumar;Labhasetwar, Vinod
通讯作者：
Labhasetwar, Vinod
DOI：
10.1021/acs.langmuir.5b02601
发表时间：
2015-10-27
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
--
作者：
Raghavan V;Vijayaraghavalu S;Peetla C;Yamada M;Morisada M;Labhasetwar V
通讯作者：
Labhasetwar V