International Journal of Nanomedicine (Mar 2021)
Synergistic Inhibition of Drug-Resistant Colon Cancer Growth with PI3K/mTOR Dual Inhibitor BEZ235 and Nano-Emulsioned Paclitaxel via Reducing Multidrug Resistance and Promoting Apoptosis
Abstract
Yali Hu,1,2,* Kunpeng Zhang,1,* Xingyao Zhu,1,* Xiuyan Zheng,1 Chao Wang,1 Xiao Niu,1 Teng Jiang,1 Xinhua Ji,1 Weilin Zhao,1 Lijuan Pang,1 Yan Qi,1 Feng Li,1,3 Li Li,4 Zhiping Xu,4 Wenyi Gu,4 Hong Zou1 1Department of Pathology, The First Affiliated Hospital, School of Medicine, Shihezi University, Key Laboratory of Xinjiang Endemic and Ethnic Diseases of the Ministry of Education of China, Xinjiang, 832002, People’s Republic of China; 2Department of Oncology, Yongcheng People’s Hospital, Henan, 476600, People’s Republic of China; 3Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 10000, People’s Republic of China; 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, Queensland, 4072, Australia*These authors contributed equally to this workCorrespondence: Hong Zou; Wenyi Gu Tel +86 13899528366; +61733464168Email [email protected]; [email protected]: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth.Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo.Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by β-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP.Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth.Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.Keywords: colon cancer, nanoemulsion, paclitaxel, BEZ235, drug-resistance
