Metal combinations ‘may help drive chemotherapy resistance’ in lung cancer
Combinations of metals inside tumour cells could help explain why some lung cancers become resistant to chemotherapy, according to new research from Durham University and Pleco Therapeutics.
The study found that several metals could act together to reduce the effectiveness of commonly used chemotherapy drugs, even when individual metals had little effect on their own.
Researchers examined metals associated with smoking and environmental pollution, including copper, manganese, zinc, chromium, cadmium and lead. At low, non-toxic levels, combinations of the metals were found to accumulate inside lung cancer cells and significantly reduce their sensitivity to chemotherapy.
However, the researchers also found that the resistance could be reversed. They tested a small molecule called MiADMSA, originally developed to treat metal poisoning, which is capable of entering cells and binding to multiple metals.
When used alongside chemotherapy, MiADMSA restored treatment sensitivity in laboratory-grown lung cancer cells. In mouse models exposed to metals, the combination also significantly reduced tumour growth.
Dr Patricia Muller is lead author of the study conducted at Durham University in cooperation with Dutch company Pleco Therapeutics. Commenting on the results, she said:
"We've found that metals inside tumour cells can work together to block chemotherapy, but the exciting part is that this resistance can be reversed. Using MiADMSA, a metal-binding compound that removes multiple metals from cells, we were able to restore treatment sensitivity."
Previous research has linked individual metals, including copper, zinc and iron, with cancer biology. However, the researchers say the new findings show that the combined effects of multiple metals may be more important than previously recognised.
The metals appear to help cancer cells withstand treatment by increasing cellular stress responses associated with reactive oxygen species. This, the researchers suggest, may protect tumour cells from some of the damage normally caused by chemotherapy.
The findings raise the possibility that chemotherapy could eventually be combined with treatments designed to alter the metal environment inside tumour cells.
Such an approach could potentially improve the effectiveness of existing cancer drugs and, if it allowed lower doses of chemotherapy to be used, reduce some of their associated side effects.
Muller said the work opened up "an exciting opportunity to develop combination therapies that could make existing cancer treatments more effective, and potentially less toxic, for patients".
The researchers saiud they believe the findings could also have relevance beyond lung cancer, because accumulation of metals has been reported also in several other cancer types.
Further research will be needed now to establish whether manipulating metal levels in tumours can provide a practical new route to overcoming chemotherapy resistance in patients.
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