Calebin A 增强 5-FU 和 TNF-β（淋巴毒素 α）对人结肠癌细胞的作用：NF-κB 的潜在作用。

Calebin A Potentiates the Effect of 5-FU and TNF-β (Lymphotoxin α) against Human Colorectal Cancer Cells: Potential Role of NF-κB.

机构信息

Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany.

Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.

出版信息

Int J Mol Sci. 2020 Mar 31;21(7):2393. doi: 10.3390/ijms21072393.

OBJECTIVE

The majority of chemotherapeutic agents stimulate NF-κB signaling that mediates cell survival, proliferation and metastasis. The natural turmeric non-curcuminoid derivate Calebin A has been shown to suppress cell growth, invasion and colony formation in colorectal cancer cells (CRC) by suppression of NF-κB signaling. Therefore, we hypothesized here that Calebin A might chemosensitize the TNF-β-treated tumor cells and potentiates the effect of 5-Fluorouracil (5-FU) in advanced CRC.

MATERIALS AND METHODS

CRC cells (HCT116) and their clonogenic 5-FU chemoresistant counterparts (HCT116R) were cultured in monolayer or alginate-based 3D tumor environment culture and were treated with/without Calebin A, TNF-β, 5-FU, BMS-345541 and DTT (dithiothreitol).

RESULTS

The results showed that TNF-β increased proliferation, invasion and resistance to apoptosis in chemoresistant CRC cells. Pretreatment with Calebin A significantly chemosensitized HCT116R to 5-FU and inhibited the TNF-β-induced enhanced efforts for survival, invasion and anti-apoptotic effects. We found further that Calebin A significantly suppressed TNF-β-induced phosphorylation and nuclear translocation of p65-NF-κB, similar to BMS-345541 (specific IKK inhibitor) and NF-κB-induced tumor-promoting biomarkers (NF-κB, β1-Integrin, MMP-9, CXCR4, Ki67). This was associated with increased apoptosis in HCT116 and HCT116R cells. Furthermore, blocking of p65-NF-κB stimulation by Calebin A was imparted through the downmodulation of p65-NF-κB binding to the DNA and this suppression was turned by DTT.

CONCLUSION

Our findings indicate, for the first time, that Calebin A chemosensitizes human CRC cells to chemotherapy by targeting of the p65-NF-κB signaling pathway.

目的

大多数化疗药物会刺激 NF-κB 信号通路，从而介导细胞存活、增殖和转移。天然姜黄素非姜黄素衍生物姜黄素 A 已被证明可通过抑制 NF-κB 信号通路来抑制结直肠癌细胞 (CRC) 的细胞生长、侵袭和集落形成。因此，我们假设姜黄素 A 可能会使 TNF-β 处理的肿瘤细胞对化疗药物更敏感，并增强 5-氟尿嘧啶 (5-FU) 在晚期 CRC 中的作用。

材料和方法

在单层或藻酸盐 3D 肿瘤环境培养物中培养 CRC 细胞 (HCT116) 及其克隆形成的 5-FU 耐药对应物 (HCT116R)，并用/不用姜黄素 A、TNF-β、5-FU、BMS-345541 和 DTT（二硫苏糖醇）处理。

结果

结果表明，TNF-β 增加了耐药 CRC 细胞的增殖、侵袭和抗凋亡能力。用姜黄素 A 预处理可显著增强 HCT116R 对 5-FU 的化疗敏感性，并抑制 TNF-β 诱导的增强生存、侵袭和抗凋亡作用。我们进一步发现，姜黄素 A 可显著抑制 TNF-β 诱导的 p65-NF-κB 磷酸化和核转位，类似于 BMS-345541（特异性 IKK 抑制剂）和 NF-κB 诱导的肿瘤促进生物标志物（NF-κB、β1-整合素、MMP-9、CXCR4、Ki67）。这与 HCT116 和 HCT116R 细胞中的凋亡增加有关。此外，通过下调 p65-NF-κB 与 DNA 的结合，DTT 可逆转姜黄素 A 对 p65-NF-κB 刺激的阻断。