Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111, Szczecin, Poland.
Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Unii Lubelskiej 1, 71-252, Szczecin, Poland.
Sci Rep. 2021 May 10;11(1):9846. doi: 10.1038/s41598-021-89128-0.
The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.
硼替佐米（BTZ）的抗癌活性在许多适应症中得到了越来越多的研究，并且在神经母细胞瘤中显示出了这种治疗方法的有前途的结果。由于 BTZ 治疗通常以周期进行，因此接受 BTZ 治疗的患者中耐药性和副作用的发展仍然是该化合物临床应用的主要挑战。常见的耐药性发展也意味着某些细胞能够在 BTZ 治疗中存活下来，并绕过使 BTZ 具有抗癌活性的分子机制。我们研究了从 BTZ 治疗中存活下来的神经母细胞瘤细胞的甲基组。我们的结果表明，BTZ 在从治疗中恢复的细胞中诱导了明显的全基因组甲基化变化。对鉴定的甲基化变化的功能分析表明，它们参与了关键的癌症病理途径。这些变化可能使细胞能够绕过 BTZ 的主要抗癌活性，并产生耐药性和增殖表型。为了研究从 BTZ 治疗中存活下来的细胞是否获得了增殖表型，我们反复处理从第一轮 BTZ 治疗中恢复的细胞。重复治疗导致细胞的非凡增殖潜力的诱导，并且随着后续治疗而增加。由于我们在从来那度胺治疗中存活下来的细胞或在相同实验条件下培养的未处理细胞中未观察到类似的效果，因此这种现象似乎是 BTZ 特异性的。总的来说，我们的结果表明，甲基化变化可能在 BTZ 耐药性的发展中起主要作用。
