Scientists headed by a team at MRC Laboratory of Medical Sciences (LMS) and Imperial College London have found that a new set of drugs can exploit a recently-revealed weakness in senescent—or ‘zombie-like’—cells, a finding that could lead to new treatments for cancer and age-associated diseases.
Senescent cells walk a tightrope, risking cell death with high levels of iron and other damaging agents, but compensating for this by overproducing a protective protein, GPX4, which staves off death. The team showed that targeting this defense mechanism removes the shield and could be used to treat diseases that are associated with senescence, including cancer. Tests showed that combining anticancer therapies with GPX4 inhibitors eliminated senescent tumor cells in models of melanoma, prostate and ovarian cancer. This approach, they say, could complement existing treatments to bring much-needed improvements for cancer patients.
Mariantonietta D’Ambrosio, PhD, a postdoctoral researcher at the LMS, is first author of the international research team’s published paper in nature cell biology, titled “Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.”
Cancers grow as a result of unconstrained cell division. But within most tumors, there is a portion that does not divide at all: senescent cells. Chemotherapy often increases the proportion of senescent cells in a tumor as it aims to stem the rapid proliferation, the team explained. However, while these senescent cells don’t directly increase the size of a tumor, they can wreak havoc in their own way.
Senescent cells, which are also a defining feature of aging conditions such as fibrosis, influence neighboring cells by secreting molecules that increase proliferation, the spread of the cancer, and unwanted immune system activity. “Senescent cells drive aging and age-related pathologies, including cancer,” the team wrote. There is therefore an increasing interest in developing drugs that directly target and kill senescent cells, in cancer and beyond. “Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal,” they continued. “Compounds that selectively kill senescent cells (senolytics) can treat different age-related pathologies.”
The study by D’Ambrosio and colleagues has identified a new approach to killing senescent cells in cancer. “Senescence was considered for a long time to be positive, because senescent cells don’t proliferate, which is the core feature of cancer,” D’Ambrosio explained. “Normal chemotherapy induces senescence blocking the proliferation of cancer cells, so the tumor doesn’t get bigger. But with time you also see the negative side of the senescent cells, because they secrete a lot of factors that influence neighboring cells and induce even more proliferation, metastasis, and recruitment of bad parts of the immune system that will provoke even more aggressiveness in the tumor. For this reason, we tried to find some drugs that were able to kill the senescent cells.”
The researchers cast a broad net in their search for new drugs that might kill senescent cells. Together with collaborators at the Department of Medicinal Chemistry at Imperial, they decided to examine covalent compounds, a class of inhibitors that can form a covalent bond with their target, which can result in the inhibition of proteins previously considered undruggable. The investigators introduced 10,000 different covalent compounds to both senescent cells and normal cells, looking for the ones that preferentially killed senescent cells and classing the drug as “senolytic,” or senescent-killing.
They narrowed their results down to just four promising compounds and found that three of them affected a particular protein, GPX4, which has a protective role in cells, helping stave off ferroptosis, a type of cell death associated with high levels of iron and destructive reactive oxygen species. To protect themselves against the high levels of iron and other ferroptosis-causing agents, senescent cells have high levels of GPX4. It is like proactively taking a painkiller so a person can keep running on an ankle. The damage and danger remains, but the immediate risks are bypassed. Removing the painkiller makes the pain unbearable.
“Senescent cells are primed for ferroptosis and upregulate GPX4 as a protective mechanism,” the team noted. Ferroptosis had only recently been revealed as a potential weakness of senescent cells. D’Ambrosio commented, “recent papers have shown this predisposition of senescent cells to ferroptosis, but it’s a new senescence vulnerability. That creates an opportunity for us to exploit. So now there is research to find senolytic drugs to kill cells through ferroptosis.”
The researchers found that blocking the activity of GPX4 removes the shield, making fatal ferroptosis unavoidable. The authors further commented, “We concentrated our studies on four chloroacetamides displaying senolytic activity in different models of senescence … GPX4 was a target of three of the four senolytic chloroacetamides. GPX4 is a glutathione peroxidase that prevents ferroptosis by reducing lipid peroxidation.”
The team tested their drugs with three different mouse models of cancer and saw improved outcomes as a result of senescent cell death in each case. Translating this to patients could be a huge asset to cancer treatments. “In mouse models we saw that these drugs reduced tumor size, and improved survival,” noted professor Jesus Gil, PhD, senior author and head of the senescence group at the LMS. “Now we need to see the effect on the immune system. Is the improvement also awakening the ‘good side’ of the immune system (T cells, natural killer cells) that helps to kill the tumor? … Once we know more, the next step is to understand which cancer cell types or specific patients might better respond to this treatment. For example, if a patient undergoing chemotherapy overexpressed GPX4 then you could use this approach in combination with existing drugs to improve efficacy.”
This approach offers a much-needed new perspective on cancer therapy, pinpointing senescent cells as an underexploited target. D’Ambrosio says it has potential to transform treatment. “Targeting senescence is a huge opportunity for cancer treatments, and ultimately it can play a supporting role in addition to chemotherapy and immunotherapy.”
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