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X-ray fluorescence maps, essential physiological element of the cell (K, in pink), and osmium, constituent of metallocifen (Os, in green), in hormone-independent bad cancer cells exposed to osmocenyl derivatives of tamoxifen. Credit: ESRF / Bohic
Some types of cancer can not be treated with conventional chemotherapy. Scientists from Inserm, CNRS, Sorbonne University, PSL University, Grenoble Alpes University and ESRF, the European Synchrotron, are working on a metallo-organic molecule Antitumor drug. Their research helped to better understand its mechanism of attack of cancer cells. This study is published in Angewandte Chemie.
Triple negative bad cancer, which accounts for 10 to 20% of bad cancers, is not powered by hormones. In fact, it is negative for estrogen and progesterone receptors and for excess HER2 protein. This means that it does not respond to hormonal treatments and antibody-based medications. Since he is more aggressive and that he often has a higher rank than other types of bad cancer, the scientific community is relentlessly trying to find a cure.
A team from Inserm, CNRS, Sorbonne University, PSL University, Grenoble Alpes University and ESRF have joined forces to study the path taken by metallocene or metallocifenic molecules, derived from the widely used drug tamoxifen, to reach cancer cells. These products were developed by Professor G. Jaouen and his group of universities at the Sorbonne and the PSL. They demonstrated their broad spectrum of effectiveness and their potential to significantly overcome drug resistance.
"We know that this molecule works because many tests have already been done, but we do not know how it manages to kill the cancer cell.That's why we want to quantify and locate the drug inside. of the cell, in order to understand its effectiveness, "says Sylvain Bohic, scientist at Inserm and lead author of the study.
Scientists have used the ESRF line of light ID16A for their research. State-of-the-art synchrotron imaging has provided a better understanding of the intracellular distribution of metallocifen, which they can follow with a resolution of 35 nanometers. "Investigations have been going on for a few years now and are finally taking advantage of the instrument's latest capabilities in both 2D and 3D cryogenic X-ray fluorescence approaches," adds Peter Cloetens, head of ID16A.
For the first time, they showed how the molecule penetrates very easily into the membrane of the cancer cell, because of its lipophilic character and that it targets an essential cellular organelle, the endoplasmic reticulum, a large organelle made of leaves and membranous tubules nucleus and extend through the cell. Then, it oxidizes and attacks different parts of the cell at the same time, leading to effective anticancer activity. "Think of it as if the organometallic molecule started many fires in different parts of the cancer cell, until the tumor cell could no longer fight it and die," Bohic says.
The results are promising because this new family of metallodrugs, which acts on several targets, could one day become an alternative to conventional chemotherapy to overcome drug resistance while controlling costs. Cisplatin, another metal-based drug widely used for the treatment of cancer, damages DNA as the primary target of the cell. Although very effective, its side effects exist and the cancer cells have developed effective mechanisms of resistance to this chemotherapy. In fact, triple negative bad cancer and other cancers, as well as recurrent cancers, are often resistant to cisplatin.
"This study is a contribution to the understanding of the alternative mechanisms of chemotherapy to cancer treatment.We are at an early stage of research, clinical trials have not yet started, but they are promising up to now, "says Professor G. Jaouen. The next step is to determine how this molecule works in healthy cells and to study toxicology.
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More information:
Florin FUS et al., Intracellular localization of an osmocenyl-tamoxifen derivative in bad cancer cells revealed by synchrotron X-ray fluorescence nanoimaging. Angewandte Chemie International Edition (2019). DOI: 10.1002 / anie.201812336
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