The early online edition in the Proceedings of the National Academy of Sciences reveals a new study, which suggests that blocking a protein in the heart that is produced under stressful conditions could be a new approach to prevent cardiac damage caused by chemotherapy.
According to earlier studies, almost a quarter of people who received the common chemotherapy drug doxorubicin have a risk of developing heart failure later on in life, yet so far it remains uncertain how this heart damage occurs.
Scientists from Ohio University now discovered in mice and cell cultures that a protein named heat shock factor-1 (HSF-1) could be the likely culprit of chemotherapy-related heart damage. HSF-1 is induced by stress, which relates to chemotherapy itself, as the treatment is stressful for the body.
Senior study author, Govindasamy Ilangovan, associate professor of internal medicine at Ohio State University explains: “We have found that a simple stress-related factor could be aggravating chemotherapy’s effect on the heart. The results are leading us toward the idea that any additional stress could hurt the heart more than what chemotherapy itself can do.”
In an animal experiment, the researchers administered two groups of mice with doxorubicin. One group consisted of normal animals, whilst the animals in the other group were genetically altered to be unable to produce HSF-1. They discovered that the hearts of mice without HSF-1 were healthier and the animals lived longer following chemotherapy than the normal mice.
The findings of a closer examination on the cellular level demonstrated that when HSF-1 is blocked in the heart, a gene is activated, which produces a protein that pumps the chemo medicine out of heart muscle cells and therefore prevents these cells from dying. Ilangovan and his team are currently working to develop drugs that could selectively inhibit HSF-1 in the heart as a possible supplementary therapy for cancer patients who receive chemotherapy.
In addition to killing cancer cells, chemotherapy can also kill other cell types in various organs. Ilangovan explained that most of the time, organs are able to regenerate cells after having been damaged, whereas heart muscle cells or cardiomyocytes cannot be regenerated. The loss of these cells can weaken the heart muscle, leading to dilated cardiomyopathy, a condition whereby the heart’s pumping action is reduced, and which can result in heart failure.
Ilangovan explained: “This work arose from that background. We are trying to identify a factor that can be targeted to prevent the cardiomyopathy.”
Earlier studies demonstrated already that doxorubicin leads to activation of HSF-1 in the heart. In order to establish the association between heat shock factor-1 and multidrug-resistance-1 or MDR1, a gene that helps the heart after chemotherapy, the team conducted various experiments in animals and cell cultures.
Experiments, in which the researchers used heart muscle cells from mice with activated HSF-1 proteins and mice without demonstrated that MDR1 was more activated in cells without the HSF-1 protein than in those with normal heart cells. They also observed that the MDR1 gene induced the production of a protein on these heart cells’ surface, which pumped doxorubicin away from the cells.
Ilangovan declared:
“This was an exciting finding. When we knock out the protein, not only is the cell death pathway prevented, but it also induces a multidrug-resistant gene, which pumps the drug away from the cells. So when HSF-1 gets activated by chemo, that leads to cardiomyocyte death. But if we knock it out, that gene comes and protects the heart.”
The team also observed the occurrence of an interaction between HSF-1 and NF-kB, another protein in the heart cells, which they were able to trace to the production of the protective gene. Ilangovan explained: “They’re sort of antagonizing each other. If HSF-1 is lower, the other protein becomes dominant. They compete for the same binding site, and when we knock out HSF-1, NF-kB can go freely bind and activate the MDR1 gene.” This also means that in the presence of HSF-1, the NF-kB protein is inhibited, which in turn blocks activation of the protective gene.
The team noted longer survival times in those mice that failed to produce HSF-1 after doxorubicin treatment. In addition they observed that images showed less chemotherapy-related damage to these mice’ hearts as compared with normal mice.
To ensure that switching off the HSF-1 protein prior to chemotherapy would not induce the multidrug-resistant gene in those cells, which could have devastating results, the team also tested breast cancer cells.
Ilangovan states that the precise timing of inhibiting HSF-1 and limiting this inhibition to the heart are crucial factors for the development of drugs to target it.
According to various studies of HSF-1, the protein can have both beneficial as well as damaging effects in the body. However, researchers have come to the overall conclusion that the timing of its activation helps to determine which effect the protein will have. If HSF-1 is activated before an injury or other damaging event it can be protective, whereas after an injury, i.e. chemotherapy with doxorubicin, the protein is generally more harmful.
Ilangovan concluded:
“I foresee that perhaps a patient would take a drug to silence HSF-1 in the heart one or two days before chemotherapy. So until the chemo is cleared out, the protein would be in the knock-down stage and no damage to the heart would occur.”
Written By Petra Rattue