How to feed cancer cells with poison
Transporter proteins on tumor cells can be used to treat cancer
Nanonews Network based on Whitehead Institute for Biomedical Research:
Cell surface transporters exploited for cancer drug delivery.
Some protein molecules present in high concentrations on the surface of many cancer cells can be used as "funnels" for "pouring" toxic molecules into cells. Scientists at the Whitehead Institute believe that overexpression of specific molecular transporters can be used to deliver drugs to cancer cells and, based on this concept, are developing a new strategy for targeting tumor cells.
"Our work suggests a new strategy for cancer treatment, which uses the ability of cancer cells to absorb something toxic that is not absorbed by a normal cell," says the head of the study, researcher at the Whitehead Institute David Sabatini, professor of biology at the Massachusetts Institute of Technology (MIT) and a researcher at the Medical Howard Hughes Medical Institute (HHMI). "As a result, this toxic molecule will kill cancer cells. Having found such transporters on the surface of cancer cells, it is possible to find a molecule that is toxic to the cell, which will be transported by one or another specific transporter. So we could get something much more selective in relation to cancer cells."
On a special line of haploid cells, scientists have identified genes that promote the entry of 3-bromopyruvate (3-bromopyruvate, 3-BrPA) into cells, a potential anti–cancer drug undergoing clinical development. 3-BrPA is believed to be an inhibitor of glycolysis, the cellular process of releasing energy by splitting glucose molecules. Since many cancer cells largely depend on a high level of glycolysis, drugs that interrupt this pathway can become effective means of combating tumors from glycolytic cells.
By screening and sequencing, the researchers identified a gene encoding the monocarboxylate transporter 1 (MCT1) protein, which is necessary and sufficient for transport into 3-BrPA cells. In fact, the level of MCT1 on the surface of glycolytic tumor cells is a predictor of the sensitivity of these cells to 3-BrPA – the higher the expression of MCT1, the more sensitive the cells are to 3-BrPA. Experiments confirm that this is true for both in vitro and in vivo models and many human cancer cell lines.
The correlation between the concentration of MCT1 and the sensitivity to 3-BrPA can be used to predict the effectiveness of the effect of this drug on specific malignant tumors.
Summing up, we can say that the study conducted by Professor Sabatini and his colleagues makes MCT1 a biomarker for 3-BrPA. Thus, in the future, if 3-BrPA is approved as a drug, it will be possible to predict whether the cancer of a particular patient will be sensitive to it by the level of expression of this molecule. No tumor without MCT1 will respond to 3-BrPA treatment.
On the left is a 3-BrPA-sensitive cancer cell with MCT1 transporter proteins expressed on its surface, which are actually a biomarker for a potential antitumor drug 3-BrPA. The entry of 3-BrPA– a glycolysis inhibitor, into the cell leads to the death of the tumor cell, as it deprives it of energy.
On the right is a 3–BrPA-resistant cancer cell that does not have MCT1 markers. No tumor without MCT1 will respond positively to 3-BrPA treatment. (Fig. wi.mit.edu )
Although so far this approach is based on the results of studying only one toxic molecule and the protein transporting it, Professor Sabatini believes that the use of this phenomenon can be significantly expanded.
The study was funded by the National Institutes of Health of the USA, the David H. Koch Institute for Integrative Cancer Research, the National Science Foundation USA and other organizations. Its details can be found on the pages of the online edition of the journal Nature Genetics: Birsoy et al., MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.
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