乳腺癌细胞对阿霉素和紫杉醇的药物耐药性差异获得。

Differential drug resistance acquisition to doxorubicin and paclitaxel in breast cancer cells.

机构信息

School of Pharmacy, Nanjing Medical University, 818 Tian Yuan East Road, Nanjing, 211166 China.

Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004 China.

出版信息

Cancer Cell Int. 2014 Dec 21;14(1):142. doi: 10.1186/s12935-014-0142-4. eCollection 2014.

BACKGROUND

Several signal transduction pathways have been reported being involved in the acquisition of P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) upon exposure to anti-cancer drugs, whereas there is evidence indicating that the expression and activity of P-gp were not equally or even reversely modulated by different drugs.

METHODS

To further illustrate this drug-specific effect, possible mechanisms that enable breast cancer cells MCF-7 to acquire MDR to either paclitaxel (PTX) or doxorubicin (DOX) were investigated in a time-dependent manner.

RESULTS

The results suggested that at least two pathways participated in this process. One was the short and transient activation of NF-κB, the second one was the relatively prolonged induction of PXR. Both PXR and NF-κB pathways took part in the PTX drug resistance acquisition, whereas DOX did not exert a significant effect on the PXR-mediated induction of P-gp. Furthermore, the property of NF-κB activation shared by DOX and PTX was not identical. An attempt made in the present study demonstrated that the acquired resistance to DOX was via or partially via NF-κB activation but not its upstream receptor TLR4, while PTX can induce the drug resistance via TLR4-NF-κB pathway.

CONCLUSIONS

To our knowledge, this report is among the first to directly compare the time dependence of NF-κB and PXR pathways. The current study provides useful insight into the distinct ability of DOX and PTX to induce P-gp mediated MDR in breast cancer. Different strategies may be required to circumvent MDR in the presence of different anti-cancer drugs.

背景

已有报道称，多种信号转导通路参与了细胞暴露于抗癌药物后获得 P-糖蛋白（P-gp）介导的多药耐药（MDR）的过程，然而有证据表明，不同药物对 P-gp 的表达和活性的调节并不均等，甚至是相反的。

方法

为了进一步说明这种药物特异性效应，以时间依赖性方式研究了使乳腺癌 MCF-7 细胞获得对紫杉醇（PTX）或阿霉素（DOX）耐药的可能机制。

结果

结果表明，至少有两条通路参与了这个过程。一条是 NF-κB 的短暂和瞬时激活，另一条是 PXR 的相对持久诱导。PXR 和 NF-κB 通路都参与了 PTX 耐药的获得，而 DOX 对 PXR 介导的 P-gp 诱导没有显著影响。此外，DOX 和 PTX 共有的 NF-κB 激活特性并不完全相同。本研究的尝试表明，对 DOX 的获得性耐药是通过或部分通过 NF-κB 激活，但不是其上游受体 TLR4，而 PTX 可以通过 TLR4-NF-κB 通路诱导耐药。