Melatonin Enhances the Chemosensitivity of Pancreatic Carcinoma Cells (PANC-1) to Cisplatin and Cetuximab through modulation of p21, p27, p53, p57, MDM2 and KRAS Genes

Abstract

We investigated the effects of melatonin, cetuximab and cisplatin treatments alone or in combination on PANC-1 cells from a human pancreatic carcinoma of ductal cell origin through cell viability and gene expressions. The cells were left for 48 h incubation after applying chemicals on the PANC-1 cells. The metabolic effects of the substances on cell viability at the end of incubation were measured by MTT assay. The gene expressions of p21, p27, p53, p57, MDM2 and KRAS were determined by RT-PCR. The use of melatonin combined with cisplatin or cetuximab increased p21 and p57 genes and decreased KRAS gene. Furthermore, melatonin combined with cetuximab increased p27 gene expression and decreased the cell viability compared to cetuximab alone. The cell viability was the lowest in cisplatin and cisplatin plus melatonin and/or cetuximab groups. The p53 were highest in the cisplatin groups while cisplatin plus melatonin decreased the p53 gene and its autoregulator MDM2 gene compared to cisplatin alone. In conclusion, melatonin in combinations with cisplatin and cetuximab enhances the tumor suppressor genes p21, p27 and p57 along with a modulation of the oncogenic gene KRAS suggesting the potential of melatonin as a therapeutic approach in combination therapy of pancreatic ductal adenocarcinoma.

Keywords

• Cetuximab
• cisplatin
• melatonin
• oncogenes
• pancreatic cancer
• tumor suppressor genes.

Melatonin, p21, p27, p53, p57, MDM2 ve KRAS Genlerinin modülasyonu yoluyla Pankreas Karsinomu Hücrelerinin (PANC-1) Cisplatin ve Cetuximab'a Kemosensitivitesini Artırır

Öz

Tek başına veya kombinasyon halinde melatonin, setuksimab ve sisplatin tedavilerinin, hücre canlılığı ve gen ekspresyonları yoluyla duktal hücre kaynaklı bir insan pankreas karsinomunun PANC-1 hücreleri üzerindeki etkilerini araştırdık. PANC-1 hücrelerine kimyasallar uygulandıktan sonra hücreler 48 saat inkübasyona bırakıldı. İnkübasyon sonunda maddelerin hücre canlılığı üzerindeki metabolik etkileri MTT tahlili ile ölçüldü. p21, p27, p53, p57, MDM2 ve KRAS'ın gen ifadeleri RT-PCR ile belirlendi. Sisplatin veya setuksimab ile kombine melatonin kullanımı, p21 ve p57 genlerini arttırdı ve KRAS genini azalttı. Ayrıca, setuksimab ile kombine edilen melatonin, tek başına setuksimab ile karşılaştırıldığında p27 gen ekspresyonunu arttırdı ve hücre canlılığını azalttı. Hücre canlılığı, sisplatin ve sisplatin artı melatonin ve/veya setuksimab gruplarında en düşüktü. p53, sisplatin gruplarında en yüksek iken, sisplatin artı melatonin, tek başına sisplatine kıyasla p53 genini ve onun otoregülatör MDM2 genini azalttı. Sonuç olarak, sisplatin ve setuksimab ile kombinasyon halinde melatonin, tümör baskılayıcı genler p21, p27 ve p57 ile birlikte onkojenik gen KRAS'ın bir modülasyonunu arttırır, bu da melatoninin pankreas duktal adenokarsinomunun kombinasyon tedavisinde terapötik bir yaklaşım olarak potansiyelini ortaya koyar.

Anahtar Kelimeler

• Cetuximab
• sisplatin
• melatonin
• onkogenler
• pankreas kanseri
• tümör baskılayıcı genler.

Kaynakça

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