Fatehi Daryoush, Soltani Amin, Ghatrehsamani Mahdi
Department of Medical Physics, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Pathol Res Pract. 2018 Jun;214(6):889-895. doi: 10.1016/j.prp.2018.04.001. Epub 2018 Apr 5.
Chemo-radio therapy (CRT) resistance is a main barrier in treating the triple negative breast cancer (TNBC). The success of conventional treatment may be ameliorated by elevating the responsiveness of the cancer cells to CRT. NVP-BEZ235 as a PI3K/AKT/mTOR dual inhibitor has been shown promising results in treating breast cancer cells. However, potential radiation-sensitizing effect of NVP-BEZ235 in TNBC remained unclear. In addition, SIRT-1 activation state and environmental cytokine were identified as being responsible for cancer cells responses to CRT. Herein, we investigate the role of interleukin 6 (IL-6) as a tumor environmental cytokine and SIRT1 in the effectiveness of NVP-BEZ235 plus radiotherapy.
TNBC cells were pre-treated with/without IL-6 and were exposed to single and combination of SRT1720 (SIRT1 activator)/EX-527 (SIRT1 inhibitor) and/or NVP-BEZ235 and/or gamma radiation. The effect of our treatments on cellular growth was determined by MTT and the cellular death and CSCs percentage were determined by Flow cytometry. Senescence detection kit was used to assay the effect of our treatments on cellular senescence induction.
Activation of SIRT1 via SRT1720 increased the efficacy of CRT in TNBC cells, especially when IL-6 exists in tumor microenvironment. Additionally, IL-6 pre-treatment followed by exposure to SRT1720 and NVP-BEZ235 significantly increased sensitivity of the cancer stem cells to radiation (p < 0.05).
Our result shows that combination of NVP-BEZ235 and SRT1720 may effectively improve late stage breast cancer cells therapeutics approach. Activation of SIRT1 and STAT3 in resistance breast cancer cells improves the in-vitro therapeutic efficacy of CRT.
化疗放疗（CRT）耐药是三阴性乳腺癌（TNBC）治疗中的主要障碍。提高癌细胞对CRT的反应性可能会改善传统治疗的效果。NVP-BEZ235作为一种PI3K/AKT/mTOR双重抑制剂，在治疗乳腺癌细胞方面已显示出有前景的结果。然而，NVP-BEZ235在TNBC中的潜在放射增敏作用仍不清楚。此外，SIRT-1激活状态和环境细胞因子被认为与癌细胞对CRT的反应有关。在此，我们研究白细胞介素6（IL-6）作为肿瘤环境细胞因子和SIRT1在NVP-BEZ235联合放疗有效性中的作用。
TNBC细胞在有或无IL-6的情况下进行预处理，然后暴露于SRT1720（SIRT1激活剂）/EX-527（SIRT1抑制剂）和/或NVP-BEZ235和/或γ射线的单一及联合处理。通过MTT法测定我们的处理对细胞生长的影响，通过流式细胞术测定细胞死亡和癌症干细胞百分比。使用衰老检测试剂盒测定我们的处理对细胞衰老诱导的影响。
通过SRT1720激活SIRT1可提高CRT对TNBC细胞的疗效，尤其是当肿瘤微环境中存在IL-6时。此外，先进行IL-6预处理，然后暴露于SRT1720和NVP-BEZ235，可显著提高癌症干细胞对辐射的敏感性（p<0.05）。
我们的结果表明，NVP-BEZ235和SRT1720联合使用可能有效改善晚期乳腺癌细胞的治疗方法。在耐药乳腺癌细胞中激活SIRT1和STAT3可提高CRT的体外治疗效果。
