Cancer makes some proteins in the body to alter their performance. One of these proteins is the ABCG2 referred to as the breast cancer resistance protein and plays a role in multi-drug resistance to chemotherapeutic agents. However, when a woman develops breast cancer it suffers a mutation and this protein does not perform adequately and carries out tasks which do not correspond.
Universidad Nacional de Colombia (UNal) Macromolecules Research Group and Ph.D. candidate, Diana Catherine Peña, explains that when a person undergoes chemotherapy the muted ABCG2 protein begins to expel medicines form the cancerous cell, reducing the effectiveness of the treatment. In face of this issue, Peña synthesized a compound which blocks the action of the ABCG2 protein so the drugs used to treat breast cancer may be effective.
World Health Organization data indicate that in 2012 breast cancer had the third highest cancer incidence in the world with 1,671,149 reported cases and a mortality total of more than have a million people. In Colombia, that same year, there were 2,649 deaths and 7,402 breast cancer cases. Furthermore, researchers estimate that for 2017 this amount tripled. In face of this scenario, increasing the possibilities for improving treatment against the disease is crucial and urgent.
A novel and powerful inhibitor
One of the main challenges of researching the ABCG2 protein is that its molecular interactions with its environment are mostly unknown. Dr. Peña says this situation hinders computational methods from identifying the compounds useful to inhibit its activity, therefore they require costly and detailed laboratory trials to, for instance, test compounds which report good activity and better assess its effects.
In order to advance in her project, she sought support on the results of the project carried out by Professor Christian Ochoa of the UNal Macromolecules Research Group, who had worked with compounds with the amide bond to suppress the ABCG2 protein.
In the research project of the Ochoa, who was also her thesis director, they demonstrated that they have great action, but are bit insoluble and hydrolyze enzymatically, in other words, when they enter into contact with body enzymes they lose stability; hence their effect is not significant.
With these results, Dr. Peña used two compounds derived from those used by Ochoa: the first has a ketone as the main element and the second is comprised by chalcones.
“We assessed these compounds to become cognizant if they had inalterable bonds which allowed them to preserve stability and activity; afterward we assembled them, changed same bonds and added fragments to increase their inhibitory activity over the protein,” said Peña.
The effectiveness of the compound was tested in breast cell lines cell in a trial measuring fluorescence. After applying the compound they added a colorant to become aware how active the protein was and verify if it blocked or not the effect of medicine transport outside the cell.
They verified that it effectively hindered the activity of the ABCG2 protein between 80% and 100 %. They also tested it on two other proteins (ABCB1 and ABCC1) also associated to resistance to multiple drugs, although in this case it only inhibited 10%, demonstrating its high selectivity. They also observed that after 120 hours, from the moment when the cancer drug enters the cancerous cell, it does not eliminate it, as for that time the protein has expelled the chemotherapeutic agent out of the cell.
Another test was the chemosensitivity test which indicates if the obtained substance works in combination with other drugs used to treat breast cancer. In trying it with one of these drugs the number of surviving cancer cells was reduced to 10%. The compound was assessed in several concentrations and they also carried out stability and solubility tests.
The following step is to assess the cytotoxicity of the compound to verify if it affects healthy cells or not. With the results obtained it is possible to project this compound as a complementary procedure for chemotherapy to improve the effectiveness of anticancer treatment in order to benefit patients, diminishing mortality rates and permanence of the disease.
The findings of Peña were strengthened by an internship at the University of Regensburg (Germany), where she also tested her compounds. Her visit coincided with a signing of a framework agreement between UNal and the University of Regensburg, allowing doctoral candidates from both institutions to spend 30% of their program abroad to acquire a double degree.
Peña complied with all the requirements both at UNal obtaining her Ph.D. in Chemical Sciences and Ph.D. in Natural Sciences from the University of Regensburg.
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