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Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy

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Abstract

Background

Recent studies have demonstrated that autophagy plays a critical role in reducing the drug sensitivity of docetaxel (DTX) therapy. Disulfiram (DSF) has exhibited potent autophagy inducing activity in multiple studies. We hypothesized that DSF co-treatment could sensitize breast cancer cells to DTX therapy via autophagy modulation.

Methods

Breast cancer cells, MCF7, and 4T1, were treated with DTX and DSF, alone and in combination. The effects were analyzed by evaluating cytotoxicity, induction of apoptosis, induction of autophagy, and reactive oxygen species (ROS) generation. In addition, the consequence of autophagy and ROS inhibition on the DTX + DSF mediated cytotoxicity was also evaluated.

Results

Significant synergism in cytotoxicity was observed with DTX + DSF combination in breast cancer cells, MCF7, and 4T1. Hyper induction of ROS and autophagy was also found with the combination treatment. ROS inhibition by N-Acetyl Cysteine (NAC), as well as autophagy inhibition by ATG5 silencing significantly reduced the autophagy level as well as cytotoxicity of the DTX + DSF combination, indicating that the induction of autophagy mediated by high ROS generation played a critical role behind the synergistic cytotoxicity.

Conclusions

This study indicates that DTX + DSF combination therapy can effectively sensitize cancer cells by hyper inducing autophagy through ROS generation and can be developed as a therapeutic strategy for cancer treatment in the future.

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Acknowledgements

We express our sincere gratitude to Dr. Kumar Sankar Bhattacharya and Dr. Syamantak Majumder for helping us with copy-editing the manuscript.

Funding

The authors like to acknowledge financial support from ‘Department of Science and Technology (DST), Govt. of India’ under the project (ECR/2016/000566/LS), as well as to BITS-Pilani for core research grant support. KLS acknowledges fellowship support from the Council of Scientific & Industrial Research (CSIR), India.

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Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Vidya Vihar, Pilani, Rajasthan, 333031, India

    K. Laxmi Swetha, Swati Sharma & Aniruddha Roy

  2. Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Vidya Vihar, Pilani, Rajasthan, 333031, India

    Rajdeep Chowdhury

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  1. K. Laxmi Swetha
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  2. Swati Sharma
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All the data presented in the study were generated in-house. No data was used from any other source. KLS and SS performed the experiments and analyzed the data. KLS, RC, and AR designed the study plan and wrote the manuscript.

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Correspondence to Aniruddha Roy.

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Swetha, K.L., Sharma, S., Chowdhury, R. et al. Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy. Pharmacol. Rep 72, 1749–1765 (2020). https://doi.org/10.1007/s43440-020-00122-1

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  • DOI: https://doi.org/10.1007/s43440-020-00122-1

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