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.
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.
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DOI：
10.2147/ijn.s290731
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发表时间：
2021
影响因子：
8
通讯作者：
Zou H
中科院分区：
文献类型：
--
作者：
Hu Y;Zhang K;Zhu X;Zheng X;Wang C;Niu X;Jiang T;Ji X;Zhao W;Pang L;Qi Y;Li F;Li L;Xu Z;Gu W;Zou H
结肠癌是全世界男性和女性的头号致命癌症，耐药性是癌症相关死亡的主要原因。联合治疗和纳米颗粒给药已被证明可以有效地克服许多癌症的耐药性。我们之前报道了负载紫杉醇（PTX）和BEZ235的纳米乳（NE）可以协同抑制结肠癌细胞的生长。在体外和体内研究NE负载PTX和BEZ235是否能克服耐药并协同抑制耐药结肠癌细胞的生长。用CCK8试剂盒检测体外处理对细胞活力的影响，用β-微管蛋白免疫荧光染色检测细胞形态变化，用Western blotting分析耐药相关蛋白，用2株耐药结肠癌细胞株HCT116-LOHP和HT29-DDP进行裸鼠异种移植的体内肿瘤生长试验。两种细胞系均对PTX敏感，而对BEZ235相对不敏感。PTX联合BEZ235可协同抑制两种细胞系的增殖。负载PTX的纳米乳（NE-PTX）将PTX的IC50降低至约为游离PTX的2/5，表明NE-PTX具有较高的抑制效果。当NE-PTX与低浓度的BEZ235 （50 nM）结合时，IC50降低到约为游离PTX的2/3。此外，与单药治疗和对照组相比，NE-PTX+BEZ235治疗增加了细胞凋亡，降低了Pgp和ABCC1的表达，减轻了肿瘤重量。这些结果表明，负载PTX+BEZ235的纳米乳可以克服耐药，提高对癌细胞增殖和肿瘤生长的抑制作用。因此，我们的研究为治疗结肠癌耐药患者提供了一种可能的新方法。
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. 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. 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. 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. Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.