Chemotherapy remains one of the most powerful tools in the fight against cancer, yet it often comes with significant long-term side effects that can dramatically affect patients' quality of life. Among the most debilitating is Chemotherapy-Induced Peripheral Neuropathy, which impacts both the central and peripheral nervous systems and affects up to 85% of cancer patients and survivors.
Docetaxel is a chemotherapy drug that kills cancer cells by disrupting microtubules, structures essential for cell division. However, microtubules are also critical for nerve function, so docetaxel can damage nerve endings, axons and mitochondria, causing neuropathic symptoms such as numbness, tingling or pain. While highly effective against advanced, metastatic and chemotherapy-resistant cancers – including androgen-independent prostate cancer – its neurotoxic side effects can be severe enough to force treatment discontinuation.
Like other chemotherapeutics, docetaxel can cause seizures and dose-dependent neuropathy, often reducing nerve signals and slowing conduction, with motor deficits typically more severe than sensory ones, particularly in breast cancer patients.
To better understand these effects, researchers from Florida Atlantic University , in collaboration with Nova Southeastern University, turned to an unlikely ally: Caenorhabditis elegans, a very tiny roundworm with a fully mapped nervous system. Using an electroconvulsive assay, the team simulated seizure-like behaviors in the worms and measured recovery times, creating a controlled platform to study docetaxel-induced neurological dysfunction. They then explored potential treatments to counteract these effects.
The researchers studied two compounds: sildenafil citrate, a well-known drug used to treat pulmonary arterial hypertension and other medical conditions involving impaired blood flow, and Resveramorph-3 (RVM-3), a new experimental compound designed based on the structure of resveratrol, a naturally occurring plant compound.
Results of the study, published in PLOS One , showed that both short-term and long-term exposure to docetaxel significantly delayed recovery from shock-induced seizure-like behavior in C. elegans. These effects parallel the motor and sensory impairments seen in cancer patients receiving taxane chemotherapy, supporting the use of this tiny worm as a model for chemotherapy-induced neurotoxicity. By demonstrating how docetaxel disrupts neuronal function and slows neurological recovery, the study offers insight into the biological basis of these side effects and establishes a system for evaluating potential protective therapies.
Importantly, findings also revealed that sildenafil citrate and RVM-3 significantly improved recovery in the worms. Sildenafil citrate appears to stabilize neuronal activity through protein kinase G signaling and potassium channel regulation, while RVM-3 showed protective effects on nerve cells even after prolonged docetaxel exposure. Both compounds reduced the severity and duration of seizure-like behaviors, suggesting their potential as therapeutic candidates for reducing chemotherapy-related neurotoxicity.
"This study shows that a tiny organism can reveal great insight about a widespread clinical problem," said Ken Dawson-Scully , Ph.D., senior author and a professor in the Department of Biological Sciences within FAU's Charles E. Schmidt College of Science . "By using C. elegans, we were able to directly model the neurological side effects of chemotherapy and rapidly test compounds that improve recovery after neurotoxic injury. This approach not only helps us understand how drugs like docetaxel disrupt nerve function, but also provides a powerful, efficient platform for identifying therapies that could one day reduce the debilitating neurological burden experienced by cancer patients."
Chemotherapy is a cornerstone of cancer treatment worldwide, with an estimated 9.8 million people receiving first-line therapy each year as of 2018. That number is projected to rise to approximately 15 million annually by 2040, reflecting a growing global cancer burden and underscoring the urgent need to better understand and address the side effects of these lifesaving treatments.
"I was very excited by how clearly we could see the neurological effects of chemotherapy and measure recovery in real time," said Paola Ximena Gonzalez-Lerma, Ph.D., first author, staff scientist in R&D at Allosite Therapeutics, and an FAU Ph.D. graduate who worked in the Dawson-Scully laboratory at Nova Southeastern University where he was a professor in the Department of Psychology and Neuroscience within the College of Psychology. "This platform lets us move quickly from observing nerve dysfunction to testing compounds that restore normal activity, all in a living system. It opens the door to asking questions that would be difficult or slow to address in traditional models, and that's incredibly motivating as we think about how these findings could translate to more effective neuroprotective strategies."
This research demonstrates how model organisms can illuminate the mechanisms of complex neurological side effects and provide a practical platform for testing potential treatments.
"Using this platform, our team has laid the groundwork for developing strategies that could allow patients to complete lifesaving chemotherapy while minimizing long-term neurological damage," said Dawson-Scully, who also serves as provost and vice president for academic affairs at FAU. "These findings represent an important step toward interventions that improve both the effectiveness and tolerability of cancer treatment."
Study co-authors are Crystal Llyod, PharmD; and Scarlet J. Park, Ph.D., Nova Southeastern University.
- FAU -
About Florida Atlantic University:
Florida Atlantic University serves more than 32,000 undergraduate and graduate students across six campuses along Florida's Southeast coast. Recognized as one of only 13 institutions nationwide to achieve three Carengie Foundation designations: R1: Very High Research Spending and Doctorate Production ," " Opportunity College and University ," and Carnegie Community Engagement Classification - FAU stands at the intersection of academic excellence and social mobility. Ranked among the Top 100 Public Universities by U.S. News & World Report, FAU is also nationally recognized as a Top 25 Best-In-Class College and cited by Washington Monthly as "one of the country's most effective engines of upward mobility." To learn more, visit www.fau.edu .
