Leaky calcium channels may underlie ‘chemobrain’

Chemotherapy has ushered in an era of prolonged survival in the face of a cancer diagnosis, yet patients report many harmful side effects from the treatment (1). Aside from the more commonly known symptoms such as nausea and hair loss, patients also report difficulty with memory, concentration, and ability to think clearly. This array of brain fog-related symptoms has been termed “chemobrain.” Up to 75 percent of cancer patients experience chemobrain during chemotherapy, and 35 percent continue to experience the symptoms for several months after chemotherapy has ended (2). Despite the prevalence of this condition, the mechanisms behind chemotherapy-induced cognitive impairment have remained a mystery.

To find the cause of chemobrain, Andrew Marks, a molecular biologist at Columbia University, teamed up with Theresa Guise, an endocrinologist at MD Anderson Cancer Center. In a new paper published in Science Translational Medicine, their team identified “leakiness” of an intracellular calcium channel as a potential underlying cause of chemobrain (3). With a molecular target identified, the researchers also tested a therapeutic drug that decreases calcium channel leakiness and showed that it improved chemobrain symptoms in mice.

Cardiologist Andrew Marks studies the function of ryanodine receptors across the heart, muscle, and brain and how these receptors stop working properly during disease.

credit: Columbia University

“Most of my work has originally been in heart and skeletal muscle, but I became interested in the brain because I knew that this channel was also in the brain,” said Marks. While studying chronic stress in rodents to model post-traumatic stress disorder, Marks discovered that, “Stress caused a leak in the channel, and it was very similar to what was documented in the heart during heart failure and arrythmias.” It became apparent to Marks that a similar mechanism might mediate different pathologies across the heart and the brain (4).

Whether a cell is in the heart, brain, or anywhere else in the body, intracellular calcium can either come from extracellular sources or from the cell’s internal calcium storage in the sarco- and endoplasmic reticulum (SR and ER) (5). Too much calcium can be toxic to a cell because it initiates many cellular processes that may be temporally inappropriate. For example, an intracellular increase in calcium levels leads to neurotransmitter release from a neuron, but this event should only occur in response to neuronal stimulation, not random dysregulation of calcium levels within a single cell.

To aid in the tight regulation of calcium levels, ryanodine receptors (RyR), which are large calcium channels, sit in the membranes of the sarco- and endoplasmic reticulum and only allow for calcium release into a cell’s cytoplasm in response to specific signals, such as muscle contraction or neuronal firing (6). But if RyR become leaky, calcium levels within a cell become dysregulated and may lead to cellular dysfunction.

To test whether chemotherapy could lead to leakiness of the RyR channel, researchers in Marks’s and Guises’s labs first developed a breast cancer model in mice. Following the standard of care for breast cancer patients, they removed the malignant tumors and treated mice with either a control substance or doxorubicin (DOX), a common chemotherapy drug. Researchers then extracted RyR channels from mouse brains and compared those treated with a control versus DOX.

The research team discovered that DOX-treated RyR channels showed physical changes to their channel structure that suggested increased leakiness. Specifically, they found that the chemotherapy-exposed RyR channels contained lower amounts of a stabilizing channel subunit. Without this subunit, RyR channels spend significantly more time in the “open” conformation that allows calcium to leak freely from the SR/ER into the cell. “The stress-induced changes put the channel into what we call a primed state, in between open and closed,” said Marks. “This makes the channel more apt to be inappropriately activated or opened and [it’s] what causes the leak.”

The researchers also showed that treatment with DOX led to impaired glucose metabolism in the brain and decreased functioning in behavioral tests of cognitive ability. DOX treatment had the same effects on animals without breast cancer, which suggests that the observed cognitive impairments and biological changes are specific to chemotherapy rather than a side effect of cancer. Plus, the team observed the same changes to RyR channels with an additional chemotherapy regimen consisting of the drugs methotrexate and 5-fluorouracil. This suggests that RyR leakiness in DOX-treated mice is not specific to DOX but is instead more broadly attributable to various forms of chemotherapy.

My hope is that the basic science [of chemobrain] gets picked up by people who are interested in patient care and gets expanded and eventually can benefit patients.
– Andrew Marks, Columbia University

With a possible mechanistic explanation for chemobrain finally in place, the researchers set out to target leaky RyR channels as a potential treatment. Fortunately, Marks already knew of a compound that fit the bill. Building off of Marks’ earlier discovery of leaky RyRs, Masunori Matsuzaki, a cardiologist at Yamaguchi University, tested the efficacy of a compound called JTV-519 in a dog model of heart failure (7, 8). The drug was successful in preventing RyR leakiness, so in 2006, Marks founded ARMGO Pharma to further develop the compound to improve solubility and reduce off-target effects.

Now named Rycal, Marks’s team evaluated whether the small molecule could decrease leakiness of RyR channels in the brain and improve cognitive impairment symptoms in chemotherapy-exposed animals. They found that treatment with Rycal led to higher levels of the RyR-stabilizing subunit, as well as significantly less leakiness. While Rycal failed to rescue normal brain glucose metabolism, the team found that Rycal-treated mice had improved learning and memory capabilities.

Huafeng Wei, an anesthesiologist at the University of Pennsylvania who was not involved in the study, noted, “If ryanodine receptor overactivation causes cognitive dysfunction in chemotherapy, then it could be treated by a ryanodine receptor inhibitor.” Wei cautioned however that increased calcium release from the ER may be a critical component of how chemotherapy drugs kill cancer cells. Therefore, said Wei, “It’s a double-edged sword.” Further research is needed to carefully evaluate whether chemotherapy drugs will still be as effective when Rycal is concurrently used to treat chemobrain.

For now, Marks’s and Guise’s research presents a long-awaited possible explanation for the basic mechanisms of the disorder. “My hope is that the basic science [of chemobrain] gets picked up by people who are interested in patient care and gets expanded and eventually can benefit patients,” said Marks.