How Blocking a Brain Chemical Can Counteract Chemotherapy's Mood Alterations
For millions of cancer patients worldwide, the powerful drug bortezomib has emerged as a life-saving treatment, particularly for multiple myeloma and mantle cell lymphoma. But for many survivors, the victory over cancer comes with a hidden price—debilitating mood disorders that can shadow their recovery 1 .
Recent groundbreaking research has uncovered that the same medication that saves their lives may also trigger anxiety and depression through a previously unknown mechanism in the brain 1 2 .
Bortezomib-induced mood alterations affect up to 30% of patients, significantly impacting their quality of life during and after treatment 1 .
The scientific community has recently turned its attention to an intriguing family of signaling molecules called the prokineticin system, which appears to play a crucial role in this troubling side effect. Even more exciting, researchers have discovered that blocking this system may offer a way to prevent these mood alterations without compromising bortezomib's cancer-fighting abilities 1 3 .
From Cancer Cells to Brain Chemistry
Bortezomib (marketed as Velcade) belongs to a class of drugs known as proteasome inhibitors. It works by disrupting the function of proteasomes—cellular complexes that break down proteins in cells 2 .
Cancer cells are particularly vulnerable to proteasome inhibition because they rely heavily on this system to manage the rapid protein production and disposal needed for their uncontrolled growth 2 .
The prokineticin system consists of two protein ligands (PK1 and PK2) and two G protein-coupled receptors (PKR1 and PKR2). While involved in various biological processes, PK2 has emerged as a key player in both inflammation and neural signaling 1 9 .
Research has revealed that PK2 is not just another chemical messenger—it occupies the critical intersection where pain, inflammation, and mood regulation meet 1 9 .
Neuroinflammation—inflammation in the brain and nervous system—has emerged as a critical mechanism linking various neurological conditions. When immune cells in the brain become activated, they release pro-inflammatory cytokines including IL-6 and TNF-α 1 .
In the context of chemotherapy, these inflammatory changes occur in key brain regions responsible for mood regulation: the prefrontal cortex, hippocampus, and hypothalamus 1 6 .
Decision-making, personality expression
Learning, memory, emotion regulation
Stress response, emotional behavior
To understand exactly how bortezomib triggers mood changes and whether targeting the prokineticin system could help, researchers designed a comprehensive mouse study published in the International Journal of Molecular Sciences in 2021 1 3 .
Mice were divided into different groups, including control groups and those receiving bortezomib. The bortezomib group received 0.4 mg/kg of the drug three times per week for four weeks 1 .
A subset of bortezomib-treated mice also received PC1, a non-peptide antagonist that blocks prokineticin receptors (PKRs) 1 .
The team conducted multiple behavioral tests including dark/light test, marble burying test, forced swim test, and sucrose preference test 1 .
After behavioral tests, researchers examined brain tissues for markers of neuroinflammation in mood-related brain regions 1 .
| Tool | Function |
|---|---|
| PC1 | Non-peptide antagonist of prokineticin receptors |
| Bortezomib (BTZ) | Proteasome inhibitor chemotherapy drug |
| Behavioral Tests | Measures anxiety and depressive-like behaviors |
| RT-PCR | Measures mRNA levels of cytokines and PK components |
Bortezomib-treated mice displayed clear signs of anxiety and depression compared to controls 1 .
| Behavioral Test | Parameter | BTZ Effect | PC1 Effect |
|---|---|---|---|
| Dark/Light Test | Time in light area | Decreased | Partial improvement |
| Dark/Light Test | Transitions | Decreased | Partial improvement |
| Forced Swim Test | Immobility time | Increased | Prevented |
| Sucrose Preference | Sweet preference | No change | No effect needed |
The prokineticin receptor antagonist not only counteracted mechanical allodynia but also prevented the development of depressive-like behavior in bortezomib-treated mice 1 .
Establish safety profile of prokineticin antagonists in humans
Determine optimal timing and dosing schedules
Confirm PC1 doesn't interfere with bortezomib's anti-cancer effects
Explore benefits for other chemotherapy-induced side effects
The discovery that targeting the prokineticin system can counteract bortezomib's mood-altering side effects represents more than just a scientific advance—it promises a future where cancer survival doesn't come at the cost of mental well-being. As research progresses, we move closer to treatments that address not just the disease, but the whole person, honoring the complex interplay between body and mind in the journey through cancer.