Smokers performed better than nonsmokers in a clinical trial for an experimental treatment for cancer? This was the intriguing question that led University of Iowa researchers and their colleagues to develop a drinking foam, infused with carbon monoxide, that increased the effectiveness of the therapy, known as autophagy inhibition, in mice and in human cells.
The results of the study were published in Advanced Science.
Drinking foam infused with carbon monoxide: a winning weapon against cancer
Finding ways to exploit the biological differences between cancer cells and healthy cells is a standard approach to designing new cancer treatments. But it's a painstaking process that requires a deep understanding of the complex biology of cancers and often a dose of unexpected insights.
Researchers have known for several decades that autophagy, which is the cell's natural recycling system, is greater in cancer cells than in healthy cells, suggesting that inhibiting autophagy could be one way to target cancer cells. However, the results of nearly 20 clinical trials testing autophagy inhibitors have been inconclusive.
“Within these clinical trials they found mixed results; there was some benefit, but for many patients there was no benefit, which pushed researchers back to the drawing board,” says James Byrne, M.D., Ph.D., assistant professor of UI Radiation Oncology and Engineering biomedical scientist and senior author of the new study.
Seeking information on why autophagy inhibition appears to work only sometimes, the researchers made the surprising discovery that smokers in two of the previous studies of autophagy inhibitors appeared to do better than nonsmokers.
“When we looked at how smokers performed in these studies, we saw an increase in the overall response in the smokers who received the autophagy inhibitors, compared to the (non-smoking) patients, and we also saw a pretty large decrease in the size of the target lesion,” says Byrne.
This was an exciting discovery for Byrne and his team because smoking is also associated with increased levels of carbon monoxide, a gas molecule that can increase autophagy in cells in a way that researchers believe can enhance l anti-cancer effect of autophagy inhibitors.
“We also know that smokers have higher levels of carbon monoxide, and while we absolutely do not recommend smoking, this suggests that elevated levels of carbon monoxide could improve the effectiveness of autophagy inhibitors. We want to take this benefit and put it into a therapeutic platform,” added Byrne, a member of the University of Iowa Holden Comprehensive Cancer Center.
The team already had such a “platform” to test their ideas. Byrne specializes in making gas-trapping materials (GEMs): foams, gels and solids made from safe, edible substances that can be infused with different gas molecules. For this study, the researchers created a drinking foam infused with carbon monoxide.
When mice with pancreatic and prostate cancer were fed carbon monoxide foam and simultaneously treated with an autophagy inhibitor, tumor growth and progression were significantly reduced in the animals.
The team also showed that combining carbon monoxide with autophagy inhibitors had a significant anti-tumor effect in prostate, lung and pancreatic cancer in Petri dishes.
Ultimately, Byrne hopes to test this approach in human clinical trials.
“The results of this study support the idea that safe, therapeutic levels of CO, which we can deliver using GEMs, can enhance the anti-tumor activity of autophagy inhibitors, opening up a promising new approach that could improve therapies for many types. of cancer.”
In another study, researchers from UAB and Vall d'Hebron identified the mechanism by which ERK5 protein kinase inhibitors impair cancer proliferation and induce cancer death.
The results, obtained using human cancer cell lines, demonstrate that ERK5 inhibition activates cytotoxic autophagy, a process that triggers cancer death, without affecting healthy cells. A combination of ERK5 inhibitors and chemotherapy could improve cancer treatment.
Cellular protein synthesis occurs in the endoplasmic reticulum. In response to various factors, such as lack of nutrients or oxygen, the endoplasmic reticulum becomes stressed, a process that can compromise cell survival.
To deal with this, a process called UPR (Unfolded Protein Response) is initiated to restore protein production and cellular normality. Among other strategies, the UPR initiates autophagy, a biological process that allows cells to degrade and recycle defective components. However, if the stress is extreme or prolonged, the UPR is not sufficient to restore protein production and the UPR leads to cytotoxic autophagy that triggers apoptosis (cell suicide).
The UPR occurs in all cells of the body, but is of particular relevance in cancer cells, which experience high levels of endoplasmic reticulum stress. The UPR and autophagy allow cancer cells to better adapt to the environment and avoid the immune system.
As a result, cancer is very sensitive to achieving a level of autophagy that is toxic to the cell. Therefore, modulation of autophagy is a new therapeutic strategy for cancer treatment: drugs that induce high levels of autophagy can cause tumor cell collapse, as well as activation of the apoptotic cell death program.
The MAP kinase protein ERK5 controls the proliferation and survival of tumor cells, being a new therapeutic target for cancer treatment. ERK5 inhibitors have shown efficacy in several cellular and tumor models, both as monotherapy and in combination with chemotherapy. However, the mechanism by which these inhibitors induce tumor cell death was unknown.
A research team from Vall d'Hebron Research (VHIR) and the Universitat Autònoma de Barcelona (UAB), led by José Miguel Lizcano, affiliated with both institutions, has discovered the mechanism by which ERK5 inhibitors cause death of tumor cells.
Using cultures of human pancreatic, endometrial and cervical cancer cells, researchers found that ERK5 regulates tumor autophagy. Thus, ERK5 inhibitors activate endoplasmic reticulum stress and the UPR (which is already elevated in tumor cells) to levels that exceed their protective effect, activating a toxic form of autophagy that ultimately causes apoptotic cell death. tumors (a process called cytotoxic autophagy).
“ERK5 inhibitors sensitize tumor cells to chemotherapy, for which our research opens a very promising line for the improvement of chemotherapy and for more effective strategies to tackle cancer,” says José Miguel Lizcano
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