Disruption of Glioblastoma Multiforme Cell Circuits with Cinnamaldehyde Highlights Potential Targets with
Shraddha Srivastava1, Ketki Patil1, Elizabeth W Thompson1
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA 30332, USA.
Abstract:
Glioblastoma multiforme (GBM) is a major aggressive primary brain tumor with dismal survival outcome and few therapeutic options. Although Temozolomide (TMZ) is a part of the standard therapy, over time, it can cause DNA damage leading to deleterious effects, necessitating the discovery of drugs with minimal side effects. To this end, we investigated the effect of cinnamaldehyde (CA), a highly purified, single ingredient from cinnamon, on the GBM cell lines U87 and U251 and the neuroglioma cell line H4. On observing similar impact on the viability in all the three cell lines, detailed studies were conducted with CA and its isomer/analog, trans-CA (TCA), and methoxy-CA (MCA) on U87 cells. The compounds exhibited equal potency when assessed at the cellular level in inhibiting U87 cells as well as at the molecular level, resulting in an increase in reactive oxygen species (ROS) and an increase in the apoptotic and multicaspase cell populations. To further characterize the key entities, protein profiling was performed with CA. The studies revealed differential regulation of entities that could be key to glioblastoma cell circuits such as downregulation of pyruvate kinase-PKM2, the key enzyme of the glycolytic pathway that is central to the Warburg effect. This allows for monitoring the levels of PKM2 after therapy using recently developed noninvasive technology employing PET [18F] DASA-23. Additionally, the observation of downregulation of phosphomevalonate kinase is significant as the brain tumor initiating cells (BTIC) are maintained by the metabolism occurring via the mevalonate pathway. Results from the current study, if translated in vivo, could provide additional efficacious treatment options for glioblastoma with minimal side effects.
Insights
Cinnamaldehyde shows potential as a novel glioblastoma treatment by inducing cancer cell death and altering key metabolic pathways. This natural compound may offer a safer alternative to current therapies like Temozolomide.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis.
- Standard therapy, Temozolomide (TMZ), can lead to DNA damage and side effects.
- There is a need for novel GBM therapeutics with improved safety profiles.
Purpose of the Study:
- To investigate the anti-cancer effects of cinnamaldehyde (CA) and its analogs on glioblastoma cell lines.
- To explore the molecular mechanisms underlying CA's action in GBM.
- To identify potential biomarkers for monitoring GBM therapy.
Main Methods:
- Treatment of U87, U251, and H4 cell lines with cinnamaldehyde (CA), trans-CA (TCA), and methoxy-CA (MCA).
- Assessment of cellular viability, reactive oxygen species (ROS) production, and apoptosis.
- Protein profiling to identify molecular targets, including pyruvate kinase-PKM2 and phosphomevalonate kinase.
Main Results:
- CA, TCA, and MCA demonstrated equal potency in inhibiting glioblastoma cell viability.
- Compounds increased ROS levels and induced apoptosis and multicaspase activity.
- CA downregulated pyruvate kinase-PKM2 (involved in Warburg effect) and phosphomevalonate kinase (involved in mevalonate pathway).
Conclusions:
- Cinnamaldehyde exhibits significant anti-glioblastoma activity by inducing cell death and modulating critical metabolic pathways.
- Downregulation of PKM2 and phosphomevalonate kinase suggests novel therapeutic strategies for GBM.
- CA represents a promising candidate for developing new glioblastoma treatments with potentially fewer side effects.
