Oncology Department, Hospital Diego Paroissien of Maipú, Mendoza, Argentina.
Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Av. Dr. Ruiz Leal s/n, Parque General San Martín, 5500, Mendoza, Argentina.
Cell Stress Chaperones. 2017 Nov;22(6):811-822. doi: 10.1007/s12192-017-0811-z. Epub 2017 Jun 12.
Neoadjuvant (or induction) chemotherapy can be used for cervical cancer patients with locally advanced disease; this treatment is followed by radical surgery and/or radiation therapy. Cisplatin is considered to be the most active platinum agent drug for this cancer, with a response rate of 20%. In order to understand how the cisplatin treatment affects the stress response, in this work, we performed an exploratory study to analyze a number of stress proteins before and after cisplatin neoadjuvant chemotherapy. The study involved 14 patients; the pre- and post-chemotherapy paired biopsies were examined by hematoxylin and eosin staining and by immunohistochemistry. The proteins evaluated were p53, P16/INK4A, MSH2, nuclear protein transcriptional regulator 1 (NUPR1), and HSPB1 (total: HSPB1/t and phosphorylated: HSPB1/p). These proteins were selected because there is previous evidence of their relationship with drug resistance. The formation of platinum-DNA adducts was also studied. There was a great variation in the expression levels of the mentioned proteins in the pre-chemotherapy biopsies. After chemotherapy, p53 was not significantly affected by cisplatin, as well as P16/INK4A and MSH2 while nuclear NUPR1 content tended to decrease (p = 0.056). Cytoplasmic HSPB1/t expression levels decreased significantly following cisplatin therapy while nuclear HSPB1/t and HSPB1/p tended to increase. Since the most significant changes following chemotherapy appeared in the HSPB1 expression levels, the changes were confirmed by Western blot. The platinum-DNA adducts were observed in HeLa cell in apoptosis; however, in the tumor samples, the platinum-DNA adducts were observed in morphologically healthy tumor cells; these cells displayed nuclear HSPB1/p. Further mechanistic studies should be performed to reveal how HSPB1/p is related with drug resistance. When the correlations of the markers with the response to neoadjuvant chemotherapy were examined, only high pre-chemotherapy levels of cytoplasmic HSPB1/p correlated with a poor clinical and pathological response to neoadjuvant cisplatin chemotherapy (p = 0.056) suggesting that this marker could be useful opening its study in a larger number of cases.
新辅助（或诱导）化疗可用于局部晚期宫颈癌患者；这种治疗后是根治性手术和/或放射治疗。顺铂被认为是这种癌症最有效的铂类药物，其反应率为 20%。为了了解顺铂治疗如何影响应激反应，在这项工作中，我们进行了一项探索性研究，在顺铂新辅助化疗前后分析了一些应激蛋白。该研究涉及 14 名患者；化疗前后配对活检标本经苏木精和伊红染色及免疫组织化学检查。评估的蛋白有 p53、P16/INK4A、MSH2、核蛋白转录调节剂 1（NUPR1）和 HSPB1（总：HSPB1/t 和磷酸化：HSPB1/p）。选择这些蛋白是因为有证据表明它们与耐药性有关。还研究了铂-DNA 加合物的形成。在化疗前活检中，这些蛋白的表达水平差异很大。化疗后，p53 不受顺铂影响，P16/INK4A 和 MSH2 也不受影响，而核 NUPR1 含量有下降趋势（p=0.056）。细胞质 HSPB1/t 表达水平在顺铂治疗后显著下降，而核 HSPB1/t 和 HSPB1/p 有上升趋势。由于化疗后 HSPB1 表达水平的变化最为显著，因此通过 Western blot 对其进行了验证。在 HeLa 细胞凋亡中观察到铂-DNA 加合物；然而，在肿瘤样本中，在形态上健康的肿瘤细胞中观察到铂-DNA 加合物；这些细胞显示核 HSPB1/p。应该进行进一步的机制研究，以揭示 HSPB1/p 与耐药性的关系。当检查标志物与新辅助化疗反应的相关性时，只有细胞质 HSPB1/p 的高化疗前水平与新辅助顺铂化疗的临床和病理反应差相关（p=0.056），这表明该标志物可能有用，建议在更多病例中进行研究。
