School of Life Science, Huzhou University, 759 Erhuan East Road, Huzhou, 313000, Zhejiang, China.
Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, No. 866 Yuhangtang Road, Xihu District, Hangzhou, 310058, Zhejiang, China.
Cell Biol Int. 2020 Feb;44(2):610-620. doi: 10.1002/cbin.11261. Epub 2019 Dec 26.
Previous reports indicated that integrins associated signals are tightly related to tumor progression. Here, we observed elevated expression of integrin α2β1 in tumor tissues from microtubule-directed chemotherapeutic drugs (MDCDs) resistant patients compared with the samples from chemosensitive patients. More importantly, we sorted the integrin α2β1 tumor cells and found those cells revealed high MDCDs resistance, whereas MDCDs shows effective cytotoxicity to those integrin α2β1 tumor cells in vitro and in vivo. Mechanistically, we demonstrated that integrin α2β1 could induce MDCDs resistance through the activation of the PI3K/AKT pathway. Applying MPEG-PLA to co-encapsulate the integrin α2β1 inhibitor E7820 and MDCDs could effectively reverse MDCDs resistance, resulting in enhanced anticancer effects while avoiding potential systemic toxicity in vitro and in vivo. In conclusion, the expression of integrin α2β1 contributes to MDCDs resistance, while applying E7820 combination treatment by MPEG-PLA nanoparticles could reverse the resistance.
先前的报告表明，整合素相关信号与肿瘤进展密切相关。在这里，我们观察到与化疗药物敏感患者的样本相比，微管导向化疗药物（MDCDs）耐药患者的肿瘤组织中整合素α2β1的表达升高。更重要的是，我们对整合素α2β1肿瘤细胞进行了分选，发现这些细胞对 MDCDs 具有高耐药性，而 MDCDs 在体外和体内对这些整合素α2β1肿瘤细胞均具有有效的细胞毒性。在机制上，我们证明整合素α2β1可以通过激活 PI3K/AKT 通路诱导 MDCDs 耐药。应用 MPEG-PLA 共包封整合素α2β1抑制剂 E7820 和 MDCDs 可以有效逆转 MDCDs 耐药性，从而增强抗癌效果，同时避免潜在的全身毒性。综上所述，整合素α2β1的表达导致 MDCDs 耐药，而应用 MPEG-PLA 纳米粒的 E7820 联合治疗可以逆转耐药性。
