Affiliation:
1. Wallace 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.
Reference34 articles.
1. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973–1991;Davis;J. Neurosurg.,1998
2. Malignant astrocytic glioma: Genetics, biology, and paths to treatment;Furnari;Genes Dev.,2007
3. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma;Stupp;N. Engl. J. Med.,2005
4. Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres;Jain;Nat. Mater.,2014
5. Mitochondrial Dysfunction in Gliomas: Pharmacotherapeutic Potential of Natural Compounds;Guntuku;Curr. Neuropharmacol.,2016