New Research Shows Celastrol Could Be a Powerful Ally Against Glioblastoma
Glioblastoma multiforme, or GBM, is one of the most aggressive and deadly brain tumors. Despite advances in surgery, chemotherapy, immunotherapy, and targeted treatments, most patients still have a poor prognosis. Scientists are increasingly looking for new approaches, and mitochondria — the cell’s energy factories — have emerged as a promising target. Mitochondria not only power cells but also control processes like oxidative stress and cell death, which are often hijacked in cancer.
The Role of Mitochondrial Dynamics
Cancer cells, including GBM, manipulate their mitochondria by changing the balance between fusion and fission. Too much mitochondrial fission can cause dysfunction and increased production of harmful molecules called reactive oxygen species (ROS), which can drive cancer growth and resistance to therapy. Targeting mitochondrial dynamics — particularly by promoting excessive fission — is being explored as a way to make cancer cells more vulnerable to treatment.
Introducing Celastrol
Celastrol is a natural compound extracted from a plant used in traditional Chinese medicine. It has shown anti-cancer effects in many studies, but its impact on mitochondrial dynamics in GBM has not been fully understood. Researchers in this new study tested whether Celastrol could disrupt mitochondrial behavior and slow down GBM progression.
How the Study Was Conducted
Scientists treated GBM cell lines with Celastrol at low doses and observed the effects on mitochondrial shape, function, oxidative stress levels, and cell growth. They also tested Celastrol in mice that had GBM tumors to see if it could slow down tumor growth and improve survival.
Celastrol Promotes Mitochondrial Fission
The study found that Celastrol caused mitochondria in GBM cells to shift from long, healthy-looking structures to shorter, fragmented ones. This effect was noticeable after just 8 to 24 hours of treatment. The researchers confirmed that Celastrol significantly decreased mitochondrial length and area, hallmarks of increased fission.
Downregulating Mitofusin-1
Celastrol worked by lowering the levels of mitofusin-1, a key protein that normally helps mitochondria fuse together. Reducing mitofusin-1 tips the balance toward fission. Other proteins involved in mitochondrial fission, like MFF and Fis1, were not significantly affected, suggesting a specific action on fusion regulation.
Loss of Mitochondrial Function
Along with the increased fission, mitochondria lost their membrane potential, an important indicator of their ability to produce energy. When mitochondrial membrane potential falls, it signals that the mitochondria are damaged and less able to support the cancer cell’s survival.
Celastrol also led to higher levels of mitochondrial ROS, especially at higher doses. Although low doses of Celastrol initially activated antioxidant defenses like Nrf2 and HMOX1, higher doses overwhelmed these defenses, pushing the cells into a state of oxidative stress. This contributed to mitochondrial damage and likely made the cancer cells more vulnerable.
Celastrol inhibited GBM cell proliferation by lowering the levels of key proteins needed for cell division, Cyclin B1 and CDK1. Without these proteins, the cancer cells could not properly cycle through division, slowing tumor growth.
In mouse models of GBM, Celastrol treatment significantly slowed tumor growth and extended survival times. Mice treated with Celastrol lived about twice as long as untreated mice, supporting the idea that Celastrol has real therapeutic potential beyond cell cultures.
Why This Matters
This study suggests that Celastrol could be repurposed as a treatment that specifically targets mitochondrial dynamics in glioblastoma. By pushing mitochondria into excessive fission, causing energy failure, and promoting oxidative stress, Celastrol weakens the cancer cells' defenses. This makes it an attractive candidate for future drug development, either alone or in combination with other therapies.
Want to learn more? Check this out!: Impact of celastrol on mitochondrial dynamics and proliferation in glioblastoma | BMC Cancer | Full Text
