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Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P-Glycoprotein

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Abstract

Objective

To investigate the potential mechanisms that curcumin reverses 5-fluorouracil (5-FU) multidrug resistance (MDR).

Methods

Cell growth and the inhibitory rate of curcumin (2–25 μg/mL) and/or 5-FU (0.05–1000 μg/mL) on human colon cancer HCT-8 and HCT-8/5-FU (5-FU-resistant cell line) were determined using cell counting kit-8 (CCK-8) assay. Apoptosis and cell cycle after 5-FU and/or curcumin treatment were detected by flow cytometry (FCM) and transmission electron microscopy (TEM). The expression of the multidrug resistance related factors p-glycoprotein (P-gp) and heat shock protein 27 (HSP-27) genes and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively.

Results

The inhibitory rate of curcumin or 5-FU on HCT-8 and HCT-8/5-FU cells proliferation at exponential phase were in a dosedependent manner, HCT-8 cell line was more sensitive to curcumin or 5-FU when compared the inhibitory rate of HCT-8/5-FU. The 50% inhibitory concentration (IC50) of combination 5-FU and curcumin (4.0 μg/mL) in HCT-8/5-FU was calculated as 179.26 μg/mL, with reversal fold of 1.85. Another IC50 of combination 5-FU and curcumin (5.5 μg/mL) in HCT-8/5-FU was calculated as 89.25 μg/mL, with reversal fold of 3.71. Synergistic effect of 5-FU and curcumin on HCT-8 and HCT-8/5-FU cells were found. The cell cycle analysis performed by FCM showed that HCT-8 and HCT-8/5-FU cells mostly accumulated at G0/G1 phase, which suggested a synergistic effect of curcumin and 5-FU to induce apoptosis. FCM analysis found that the percentage of apoptosis of cells treated with curcumin, 5-FU and their combination were significantly increased compared to the control group (P<0.05), and the percentage of apoptosis of the combination groups were slightly higher than other groups (P<0.05). The mRNA levels of P-gp (0.28±0.02) and HSP-27 (0.28±0.09) in HCT-8/5-FU cells treated with combination drugs were lower than cells treated with 5-FU alone (P-gp, 0.48±0.07, P=0.009; HSP-27, 0.57±0.10, P=0.007). The protein levels of P-gp (0.25±0.06) and HSP-27 (0.09±0.02) in HCT-8/5-FU cells treated with combination drugs were decreased when compared to 5-FU alone (P-gp, 0.46±0.02, P=0.005; HSP-27, 0.43±0.01, P=0.000).

Conclusions

Curcumin can inhibit the proliferation of human colon cancer cells. Curcumin has the ability of reversal effects on the multidrug resistance of human colon cancer cells lines HCT-8/5-FU. Down-regulation of P-gp and HSP-27 may be the mechanism of curcumin reversing the drug resistance of HCT-8/5-FU to 5-FU.

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Acknowledgement

Special thanks to Urumqi OE Biotech Co. Ltd. for their technical assistances in this study.

Author information

Authors and Affiliations

  1. Second Department of Oncology, Traditional Chinese Medicine Hospital of Xinjiang Uyghur Autonomous Region, Uyghur, 830000, China

    Wen-ting He, Yan-hua Zhu, Patima Abulimiti, Fan-ye Zeng, Li-ping Zhang, Ling-juan Luo, Xin-mei Xie & Hong-liang Zhang

  2. Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Tong Zhang

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  1. Wen-ting He
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  2. Yan-hua Zhu
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  3. Tong Zhang
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Correspondence to Hong-liang Zhang.

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Supported by China Science Fund of Clinical Oncology (No. Y-L2014-002)

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11655_2018_2997_MOESM1_ESM.pdf

Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating HSP-27 and P-gp

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He, Wt., Zhu, Yh., Zhang, T. et al. Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P-Glycoprotein. Chin. J. Integr. Med. 25, 416–424 (2019). https://doi.org/10.1007/s11655-018-2997-z

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