Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cellsReport as inadecuate




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Molecular Cancer

, 11:25

First Online: 26 April 2012Received: 11 October 2011Accepted: 12 April 2012

Abstract

BackgroundMetastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and-or develop novel compounds is mandatory. Pemetrexed Alimta®, MTA is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer NSCLC, and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet.

ResultsIn the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and –independent apoptosis. We show that an increment of the intracellular reactive oxygen species ROS and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-L-Cysteine NAC to blockage of ROS and p53-defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 up-regulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis.

ConclusionsWe found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and –independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma.

KeywordsPemetrexed MTA Antifolates DNA damage Apoptosis Melanoma AbbreviationsMTAPemetrexed: Alimta®

NSCLCNon Small Cell Lung Cancer

ROSReactive Oxygen Species

NACN-Acetyl-L-Cysteine

Cyt-cCytochrome-c

AIFApoptosis Inducing Factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-11-25 contains supplementary material, which is available to authorized users.

Aitziber Buqué, Jangi Sh Muhialdin contributed equally to this work.

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Author: Aitziber Buqué - Jangi Sh Muhialdin - Alberto Muñoz - Begoña Calvo - Sergio Carrera - Unai Aresti - Aintzane Sancho - I

Source: https://link.springer.com/article/10.1186/1476-4598-11-25







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