J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA,
Department of Chemical Engineering, University of Florida, Gainesville, FL, USA,
Int J Nanomedicine. 2018 Aug 23;13:4771-4779. doi: 10.2147/IJN.S171130. eCollection 2018.
Overcoming resistance to antimitotic drugs, such as paclitaxel (PTX), would represent a major advance in breast cancer treatment. PTX induces mitotic block and sensitive cells exit mitosis dying by mitotic catastrophe. Resistant cells remain in block and continue proliferation after drug decay, denoting one of the PTX resistance mechanisms. Mild hyperthermia (HT) triggers mitotic exit of PTX-pretreated cells, overcoming PTX resistance and suggesting HT-forced mitotic exit as a promising strategy to potentiate PTX.
Superparamagnetic iron oxide nanoparticles (SPIONs) were used to deliver mild HT at 42°C in PTX-pretreated breast adenocarcinoma MCF-7 cells sensitive and resistant to PTX. To evaluate mechanism of cell death, cells were classified based on nuclear morphology into interphase, mitotic, micronucleated, and apoptotic. The combined PTX→SPION treatment resulted in an increase in the percentage of micronucleated cells, an indication of forced mitotic exit. Importantly, in PTX-resistant cells, the combination therapy using SPION HT helps to overcome resistance by reducing the number of cells relative to the control.
SPION HT potentiates PTX by significantly reducing cell survival, suggesting potential of combined treatment for future clinical translation.
克服抗有丝分裂药物（如紫杉醇（PTX））的耐药性将是乳腺癌治疗的重大进展。PTX 诱导有丝分裂阻滞，敏感细胞通过有丝分裂灾难退出有丝分裂而死亡。耐药细胞在药物衰减后仍处于阻滞状态并继续增殖，这表明了 PTX 耐药机制之一。轻度热疗（HT）可引发 PTX 预处理细胞的有丝分裂退出，克服 PTX 耐药性，并提示 HT 强制有丝分裂退出是增强 PTX 的有前途的策略。
超顺磁氧化铁纳米颗粒（SPION）用于在对 PTX 敏感和耐药的乳腺癌腺癌细胞 MCF-7 中以 42°C 的温度进行温和 HT。为了评估细胞死亡的机制，根据核形态将细胞分为间期、有丝分裂期、微核期和凋亡期。PTX→SPION 联合治疗导致微核细胞的百分比增加，表明强制有丝分裂退出。重要的是，在 PTX 耐药细胞中，SPION HT 的联合治疗通过减少与对照相比的细胞数量有助于克服耐药性。
SPION HT 通过显著降低细胞存活率增强 PTX，表明联合治疗具有未来临床转化的潜力。
