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Investigating the use of retinoids and epigenetic modification agents as new therapeutic strategies for the treatment of pancreatic cancer.

机译:研究使用维甲酸和表观遗传修饰剂作为治疗胰腺癌的新治疗策略。

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摘要

New therapeutic strategies are needed to improve the outcome and the quality of life for pancreatic cancer (PC) patients. This study aimed to investigate new treatment strategies for PC by assessing the potential role of retinoids and epigenetic drugs both in vitro and in an animal model of PC.Aberrant retinoid signaling is associated with carcinogenesis, and has been identified in PC. The role of key retinoid signaling components implicated in retinoid resistance, CRBP1, RARα and RARB, were investigated. CRBP1 expression was downregulated in the majority of PC cell lines and human samples. Re-expression of epigenetically silenced CRBP1 in MiaPaCa2 cells, which are resistant to retinoid treatment, did not increase the sensitivity of these cells to retinoid treatment. We demonstrated that the normal pancreatic cell line, HPDE, was sensitive to retinoid treatment and did not express RARB due to epigenetic silencing, while concomitant loss of RARα function did not reduce retinoid sensitivity in these cells. The effect of a K-ras point mutation in inducing aberrant retinoid signaling in PC was also investigated, as treatment with inhibitors of K-ras activity has been reported to diminish retinoid-induced differentiation in other cancers. However, a reduction in retinoid sensitivity was not observed in HPDE cells harboring mutant K-ras. These data suggest that CRBP1, RARα, RARB and the K-ras point mutation are unlikely to initiate retinoid resistance in PC. Combination treatment with epigenetic drugs, Histone Deacetylases inhibitors (SAHA and TSA) and/or DNA Methyltransferase Inhibitors (5-AZA-dc), decreased MiaPaCa2 cell proliferation and induced cell cycle arrest in vitro. The efficacy of 5-AZA-dc and SAHA was examined in a PC mouse model, which demonstrated that epigenetic treatment significantly increased the tumour Lag period but did not decrease the tumour growth rate. This suggests that epigenetic therapy alone may not be effective for the treatment of PC in vivo but may be more effective in combination with chemotherapeutic agents. Further studies are necessary to elucidate the mechanisms by which PC remains resistant to retinoid-based therapies, and to design and implement a more targeted delivery system to combat this devastating disease.
机译:需要新的治疗策略来改善胰腺癌(PC)患者的预后和生活质量。这项研究旨在通过评估类维生素A和表观遗传药物在体外和动物模型中的潜在作用来研究PC的新治疗策略。异常的类维生素A信号传导与癌变有关,并已在PC中得到鉴定。研究了关键类视黄醇信号转导成分在类视黄醇抗性中的作用,CRBP1,RARα和RARB。在大多数PC细胞系和人类样品中,CRBP1表达下调。在对类维生素A处理有抵抗力的MiaPaCa2细胞中表观遗传沉默CRBP1的重新表达并没有增加这些细胞对类维生素A处理的敏感性。我们证明正常胰腺细胞系HPDE对类视色素治疗敏感,并且由于表观遗传沉默而未表达RARB,而伴随的RARα功能丧失并没有降低这些细胞的类视色素敏感性。还研究了K-ras点突变在PC中诱导异常类维生素A信号传导的作用,因为据报道,用K-ras活性抑制剂治疗可减少类维生素A诱导的其他癌症分化。然而,在带有突变体K-ras的HPDE细胞中未观察到类维生素A敏感性的降低。这些数据表明CRBP1,RARα,RARB和K-ras点突变不太可能在PC中引发类维生素A耐药性。与表观遗传药物,组蛋白脱乙酰基酶抑制剂(SAHA和TSA)和/或DNA甲基转移酶抑制剂(5-AZA-dc)联合治疗可降低MiaPaCa2细胞增殖并诱导体外细胞周期停滞。在PC小鼠模型中检查了5-AZA-dc和SAHA的功效,这表明表观遗传治疗显着延长了肿瘤滞后期,但并未降低肿瘤的生长速度。这表明,单独的表观遗传疗法可能无法有效治疗体内PC,但与化学治疗剂联合使用可能更有效。有必要进行进一步的研究来阐明PC维持对类视黄醇疗法的耐药性的机制,并设计和实施更具针对性的递送系统以对抗这种破坏性疾病。

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