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Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction

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Abstract

Purpose

Paclitaxel is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). However, drug-resistance remains a major problem. Honokiol is a natural component which has been found to exhibit anti-tumor activity. Paclitaxel and honokiol have been reported to be able to induce paraptosis. The aim of this study was to investigate whether honokiol can reverse paclitaxel resistance by inducing paraptosis in NSCLC cells.

Methods

NSCLC cell lines H1650 (paclitaxel-sensitive), H1299 and H1650/PTX (intrinsic and acquired paclitaxel-resistant, respectively) were used to assess the cytotoxic effects of paclitaxel and honokiol. Light and transmission electron microscopy were performed to detect cytoplasmic vacuolation. In vitro cell viability and clonogenic survival assays, as well as in vivo xenograft assays were conducted to test synergistic killing effects of paclitaxel and honokiol on NSCLC cells. Western blotting, flow cytometry and immunofluorescence were performed to evaluate paraptosis-regulating mechanisms.

Results

We found that combination treatment with paclitaxel and honokiol synergistically killed H1650, H1299 and H1650/PTX cells by inducing paraptosis, which is characterized by cytoplasmic vacuolation. Moreover, paclitaxel/honokiol treatment resulted in a significant growth delay in H1299 xenograft tumors that showed extensive cytoplasmic vacuolation. Mechanistically, proteasomal inhibition-mediated endoplasmic reticulum (ER) stress and unfolded protein responses leading to ER dilation, and the disruption of intracellular Ca2+ homeostasis and mitochondrial Ca2+ overload resulting in mitochondrial disfunction, were found to be involved in paclitaxel/honokiol-induced paraptosis. Cellular protein light chain 3 (LC3) may play an important role in paclitaxel/honokiol induced cytoplasmic vacuolation and NSCLC cell death.

Conclusions

Combination of honokiol and paclitaxel may represent a novel strategy for the treatment of paclitaxel-resistant NSCLC.

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Acknowledgements

The authors would like to thank the Institute of Medical Science of Jiangsu University for their technical assistance and instrument support.

Funding

This work was partially supported by the National Youth Science Foundation of China (Grant No. 81402485).

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Authors and Affiliations

  1. Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China

    Xiao-Qin Li & Jing Ren

  2. Center of Experimental Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China

    Yi Wang & Qian Jiang

  3. Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China

    Jin-Yu Su, Yu-Min Zhu, Chen-Guo Chen & Jian Li

  4. Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China

    Wei-Guo Long

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  1. Xiao-Qin Li
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Correspondence to Jian Li.

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All experimental procedures were conducted in accordance with the Chinese legislation regarding experimental animals and were approved by the Institutional Animal Care and Use Committee of the Jiangsu University.

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Li, XQ., Ren, J., Wang, Y. et al. Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction. Cell Oncol. 44, 135–150 (2021). https://doi.org/10.1007/s13402-020-00557-x

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