利用NF-κB 抑制劑Platonin增加乳癌對化學治療的敏感性

多種臨床抗癌藥物 (如Doxorubicin) 在施打過幾個療程後，往往會產生抗藥性導致治療困難及預後不佳；而先前研究顯示發炎微環境的生成，也是造成癌細胞抗藥性的重要因素之一。因此，本研究的目的在探討(1)抗癌藥物是否會誘導發炎微環境的生成；(2)藉由調節轉錄因子Nuclear factor-κB (NF-κB)是否可以改善發炎微環境形成；(3)具抗藥性的癌細胞是否能透過合併NF-κB抑制劑增加藥物的敏感性。本研究發現，使用抗乳癌藥物Doxorubicin處理乳癌細胞株SKBR3後，與活化發炎微環境形成有關的調節因子NF-κB，會受到活化而有劑量依賴性的影響；進一步分析也發現，Doxorubicin處理也會誘導促發炎細胞激素TNF-?恁BIL-1β及IL-6的產生，尤其是IL-6的分泌會隨Doxorubicin處理時間增長有明顯的上升。而且藉由合併NF-κB抑制劑Platonin及PDTC，能有效抑制Doxorubicin誘發的NF-κB活化及IL-6的表現。進一步實驗顯示，NF-κB 抑制劑也能有效阻斷受到自體分泌活化的IL-6路徑，如STAT3的磷酸化及其轉錄的相關蛋白質，包括抗凋亡蛋白Survivin、Bcl-xL及抗藥性蛋白MDR-1的表現。因抗凋亡蛋白下降的結果，在細胞毒性試驗中(SRB assay 及Trypan blue exclusion assay)可觀察到，合併Doxorubicin與NF-?羠抑制劑能有效增加活化細胞凋亡路徑的Caspase-3及PARP1表現，增強對乳癌細胞株SKBR3的毒殺能力。此外，對照於SKBR3的結果，分析野生型乳癌細胞株MCF-7及抗藥型MCF-7/ADR的IL-6及MDR-1表現狀況，發現MCF-7/ADR較MCF-7細胞株具有更高的IL-6及MDR-1表現。綜合以上結果顯示，透過合併Doxorubicin與NF-?羠抑制劑能有效降低發炎微環境的發生，進而避免癌細胞產生抗藥性問題，提高治療的效果。

關鍵字

乳癌；化學治療； NF-kB ； Platonin

並列摘要

Clinical data showed that most of patients receiving several cycles of anticancer drugs, such as doxorubicin, had the symptoms of drug resistance and poor prognosis. Previous studies also revealed that inflammatory microenvironment contributes to the development of drug resistance. Therefore, aims of this study are: explore (1) if anticancer drugs can induce inflammatory microenvironment formation; (2) if regulation of a key inflammatory related transcription factor nuclear factor kappa B (NF-κB) can mediate anticancer drug induced inflammation; and (3) if NF-κB inhibitors sensitize the drug-resistant cancer cell line toward anticancer drugs. In this study, NF-κB was activated in breast cancer cell line SKBR-3 by treatment with doxorubicin. Further study showed that secretion of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were be induced by doxorubicin treatment. Especially, the release level of IL-6 was increased while prolonged treatment of doxorubicin was applied. Combined treatment of Doxorubicin with two NF-κB inhibitors (platonin and PDTC) effectively blocked doxorubicin-induced NF-κB activation and IL-6 secretion. Furthermore, NF-κB inhibitors attenuated the stimulation of IL-6 through decreasing phosphorylated STAT3. This attenuation can affect the downstream signal transduction pathway of STAT3, which related to apoptosis and drug resistant. Proteins involved in these pathway including Survivin, Bcl-xL, and MDR-1. Consequently, combined treatment of doxorubicin with NF-κB inhibitors significantly increased the activation of Caspase-9, Caspase-3 and PARP, which enhanced sensitivity of SKBR-3 cells to Doxorubicin. In study of MCF-7/wt and MCF-7/ADR cell lines, RT-qPCR revealed high expression level of IL-6 and MDR-1 gene expression was detected in MCF-7/ADR cells compared to MCF-7/wt. All the data indicated that promotion of inflammatory microenvironment would occur after anticancer drug treatment and it would contribute to drug resistant. Blockage of inflammation tumor-associated microenviroment can enhance the sensitivity of cancer cells to anti cancer drugs.

並列關鍵字

Breast cancer ； Chemotherapeutic agents ； NF-kB ； Platonin

參考文獻

1. Philip, M., D.A. Rowley, and H. Schreiber, Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol, 2004. 14(6): p. 433-9.

2. Nathan, C., Points of control in inflammation. Nature, 2002. 420(6917): p. 846-52.

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利用NF-κB 抑制劑Platonin增加乳癌對化學治療的敏感性

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