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双 PI3 激酶/mTOR 抑制剂 BEZ235 逆转 ABCB1 过表达的卵巢和胰腺癌细胞系对阿霉素的耐药性。

A dual PI3 kinase/mTOR inhibitor BEZ235 reverses doxorubicin resistance in ABCB1 overexpressing ovarian and pancreatic cancer cell lines.

机构信息

VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States.

VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States.

出版信息

Biochim Biophys Acta Gen Subj. 2020 Jun;1864(6):129556. doi: 10.1016/j.bbagen.2020.129556. Epub 2020 Feb 14.

DOI:10.1016/j.bbagen.2020.129556
PMID:32061787
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10845210/
Abstract

BACKGROUND

Multi-drug resistance (MDR) develops because cancer cells evade toxicity of several structurally unrelated drugs. Besides other mechanisms, MDR is linked to the overexpression of ATP Binding Cassette (ABC), transporters, among which ABCB1 is the best characterized one. Since overactivation of PI3K/Akt/mTOR plays a pivotal role in the growth of human cancers, we hypothesized whether dual PI3K and mTOR inhibitor, BEZ235 (BEZ, dactolisib) reverses resistance to doxorubicin (DOX).

METHODS

Ovarian (A2780) and pancreatic (MiaPaca2) cancer cells were used to generate DOX-resistant clones by overexpressing ABCB1 or stepwise treatment of DOX. Intracellular accumulation of DOX was measured by flow cytometry after treatment with BEZ.

RESULTS

BEZ treatment caused an increase in intracellular levels of DOX which was almost identical to the naïve parental cell lines. BEZ was found to be a weak substrate for ABCB1 as demonstrated by minimal increase in ATPase activity. BEZ treatment caused a dose-dependent decrease in cell viability in combination with DOX, which was associated with an increase in cleaved PARP expression in the drug resistant clones.

CONCLUSIONS

These results suggest that BEZ is a non-substrate inhibitor of ABCB1 and is able to effectively re-sensitize cells overexpressing ABCB1 to the effects of DOX.

GENERAL SIGNIFICANCE

Dual PI3 Kinase/mTOR inhibitor, BEZ, has the potential to reverse MDR in cancer patients.

摘要

背景

多药耐药性（MDR）的产生是因为癌细胞逃避了几种结构上无关的药物的毒性。除了其他机制外，MDR 还与 ATP 结合盒（ABC）转运体的过度表达有关，其中 ABCB1 是研究最为透彻的一种。由于 PI3K/Akt/mTOR 的过度激活在人类癌症的生长中起着关键作用，我们假设双重 PI3K 和 mTOR 抑制剂 BEZ235（BEZ，dactolisib）是否能逆转多柔比星（DOX）的耐药性。

方法

使用卵巢（A2780）和胰腺（MiaPaca2）癌细胞通过过度表达 ABCB1 或逐步用 DOX 处理来生成 DOX 耐药克隆。用 BEZ 处理后通过流式细胞术测量 DOX 的细胞内积累。

结果

BEZ 处理导致 DOX 的细胞内水平增加，几乎与原始亲本细胞系相同。结果表明 BEZ 是 ABCB1 的弱底物，因为其 ATP 酶活性的增加微不足道。BEZ 处理与 DOX 联合使用时，以剂量依赖的方式降低细胞活力，这与耐药克隆中裂解的 PARP 表达增加有关。

结论

这些结果表明，BEZ 是非 ABCB1 的底物抑制剂，能够有效地使过度表达 ABCB1 的细胞重新对 DOX 的作用敏感。

一般意义

双重 PI3 激酶/mTOR 抑制剂 BEZ 有可能逆转癌症患者的多药耐药性。

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