Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation
Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation
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DOI：
10.1007/s11033-022-07192-9
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发表时间：
2022-01
影响因子：
2.8
通讯作者：
N. Okuni;Y. Honma;T. Urano;K. Tamura
中科院分区：
文献类型：
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作者：
N. Okuni;Y. Honma;T. Urano;K. Tamura
背景尽管胰腺癌的治疗策略已经有所改进，但在过去的十年中，总生存率并没有显著提高。因此，更好的治疗方案的建立仍然是一个高度优先级。MethodsPancreatic cancer cell lines were incubated with romidepsin，组蛋白去乙酰化酶的抑制剂，和他莫昔芬，和他们对细胞生长，信号传导和基因表达的影响进行了分析。人胰腺癌CFPAC 1细胞的异种移植物与罗米地辛和他莫昔芬，以评估其对肿瘤growth.ResultsThe罗米地辛和他莫昔芬诱导的胰腺癌细胞的生长的抑制作用被有效地减少N-乙酰半胱氨酸和α-生育酚，分别。联合处理可显著诱导活性氧的产生和线粒体脂质过氧化，N-乙酰半胱氨酸和α-生育酚可抑制上述作用。他莫昔芬增强罗米地辛诱导的细胞衰老。在用罗米地辛处理的胰腺癌细胞中，FOXM 1表达显著下调，并且他莫昔芬进一步降低了用罗米地辛处理的细胞中的FOXM 1表达。FOXM 1抑制剂Siomycin A可诱导胰腺癌细胞衰老。在敲低FOXM 1表达的siRNA。ConclusionSince FOXM 1被用作胰腺癌的预后标志物和治疗靶点，临床上可用的药物罗米地辛和他莫昔芬的组合可被考虑用于治疗胰腺癌患者。
BackgroundAlthough improvement has been made in therapeutic strategies against pancreatic carcinoma, overall survival has not significantly enhanced over the past decade. Thus, the establishment of better therapeutic regimens remains a high priority.MethodsPancreatic cancer cell lines were incubated with romidepsin, an inhibitor of histone deacetylase, and tamoxifen, and their effects on cell growth, signaling and gene expression were analyzed. Xenografts of human pancreatic cancer CFPAC1 cells were medicated with romidepsin and tamoxifen to evaluate their effects on tumor growth.ResultsThe inhibition of the growth of pancreatic cancer cells induced by romidepsin and tamoxifen was effectively reduced by N-acetyl cysteine and α-tocopherol, respectively. The combined treatment greatly induced reactive oxygen species production and mitochondrial lipid peroxidation, and these effects were prevented by N-acetyl cysteine and α-tocopherol. Tamoxifen enhanced romidepsin-induced cell senescence. FOXM1 expression was markedly downregulated in pancreatic cancer cells treated with romidepsin, and tamoxifen further reduced FOXM1 expression in cells treated with romidepsin. Siomycin A, an inhibitor of FOXM1, induced senescence in pancreatic cancer cells. Similar results were obtained in knockdown of FOXM1 expression by siRNA.ConclusionSince FOXM1 is used as a prognostic marker and therapeutic target for pancreatic cancer, a combination of the clinically available drugs romidepsin and tamoxifen might be considered for the treatment of patients with pancreatic cancer.