When researchers at the University of S\u00e3o Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy.
According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets.
\u201cPrevious research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,\u201d said \u00c9rica Aparecida de Oliveira, a postdoctoral scholar at USP\u2019s School of Pharmaceutical Sciences (FCF).
As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism.
DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by Jos\u00e9 Agust\u00edn Pablo Quincoces Su\u00e1rez, a professor at Bandeirantes University (UNIBAN).
\u201cExperiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,\u201d Oliveira said.
To unpack DM-1\u2019s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker\u2019s and brewer\u2019s yeast.
\u201cThis yeast\u2019s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,\u201d Oliveira said.
The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment.
The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP.
\u201cWe then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,\u201d Oliveira said.
The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR).
The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients.
\u201cWe performed a data mining exercise to find genes with altered expression during melanoma progression,\u201d Oliveira said. \u201cWe identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.\u201d
In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells.
In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells.
\u201cLike curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,\u201d Oliveira said.
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