Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction
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ORIGINAL ARTICLE
Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction Xiao-Qin Li 1 & Jing Ren 1 & Yi Wang 2 & Jin-Yu Su 3 & Yu-Min Zhu 3 & Chen-Guo Chen 3 & Wei-Guo Long 4 & Qian Jiang 2 & Jian Li 3 Received: 13 March 2020 / Revised: 20 August 2020 / Accepted: 26 August 2020 # International Society for Cellular Oncology 2020
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. Keywords Non-small cell lung cancer . paclitaxel . drug resistance . honokiol . paraptosis . cytoplasmic vacuolation
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00557-x) contains supplementary material, which is available to authorized users. * Jian Li [email protected]; [email protected] 1
Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
2
Center of Experimental Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
3
Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University
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