Melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (afmk) enhance chemosensitivity to gemcitabine in pancreatic carcinoma cells (PANC-1)

Abstract

BACKGROUND: Gemcitabine is a standard chemotherapeutic agent for patients suffering from pancreatic cancer. However, the applied therapy is not effective due to the resistance of tumor cells to cytostatics, caused by inefficiency of the apoptotic mechanisms. Herein, we present the hypothesis that melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) modify the effect of gemcitabine on PANC-1 cells and that this phenomenon is dependent on the modulation of apoptosis.

METHODS: PANC-1 cells have been incubated with melatonin, AFMK or gemcitabine alone or in combination to determine the cytotoxity and proliferative effects. In subsequent part of the study, cells were harvested, the proteins were isolated and analyzed employing immunoprecipitation/immunoblotting.

RESULTS: Incubation of PANC-1 cells with gemcitabine resulted in upregulation of pro-apoptotic bax and caspases proteins expression, downregulation of anti-apoptotic Bcl-2, heat shock proteins (HSPs) and modulation of cellular inhibitors of apoptosis (IAPs). Both melatonin and AFMK administered to PANC-1 in combination with gemcitabine inhibited the production of HSP70 and cIAP-2 as compared to the results obtained with gemcitabine alone. These changes were accompanied by upregulation of Bax/Bcl-2 ratio and reduction of procaspases-9 and -3 abundance, followed by an increase in the formation of active caspase of PANC-1 cells with combination of gemcitabine plus low doses of melatonin or AFMK led to enhanced cytotoxicity and resulted in the inhibition of PANC-1 cells growth as compared to effects of gemcitabine alone.

CONCLUSION: Melatonin and AFMK could improve the anti-tumor effect of gemcitabine in PANC-1 cells presumably through the modulation of apoptotic pathway.

 

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See also:

- Official Web Site: The Di Bella Method;

- About Melatonin - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- The Di Bella Method (A Fixed Part - Cyclophosphamide and/or Hydroxyurea tablets, one or two per day);

- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;

- The Di Bella Method Increases by the 30% the survival rate for Pancreas tumors and for this reason should be proposed as first line therapy for this type of cancer;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis.