gambogic-acid and Glioblastoma

The blood-brain barrier (BBB) inhibits the delivery of macromolecular chemotherapeutic drugs to brain tumors, leading to low utilization rates and toxic side effects to surrounding tissues and organs. Ultrasonic targeted microbubble destruction (UTMD) technology can open the BBB, leading to a new type of drug delivery system with particular utility in glioma.. We have developed a new type of drug-loaded microbubble complex based on poly(lactic-co-glycolic acid) (PLGA) that targets gambogic acid (GA) to the area of brain tumors through UTMD.. GA/PLGA nanoparticles were prepared by the double emulsification method, and cationic microbubbles (CMBs) were prepared by a thin film hydration method. The GA/PLGA-CMB microbubble complex was assembled through electrostatic attractions and was characterized chemically. The anti-glioblastoma effect of GA/PLGA-CMB combined with focused ultrasound (FUS) was evaluated by biochemical and imaging assays in cultured cells and model mice.. GA/PLGA-CMB combined with FUS demonstrated a significant inhibitory effect on glioblastoma cell lines U87 and U251 as compared with controls (P<0.05). Tumor access and imaging analyses demonstrated that administration of GA/PLGA-CMBs combined with FUS can open the BBB and target the treatment of glioblastoma in a mouse model, as compared with control groups (P<0.05).. The combination of PLGA-CMB with FUS provides an effective and biocompatible drug delivery system, and its application to the delivery of GA in a mouse glioblastoma model was successful.

Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Drug Delivery Systems; Glioblastoma; Glioma; Mice; Microbubbles; Xanthones

Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating gambogic acid-induced cytotoxic effects in glioma cells.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Cell Line, Tumor; ErbB Receptors; Glioblastoma; Humans; Mechanistic Target of Rapamycin Complex 1; Membrane Glycoproteins; Multiprotein Complexes; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Tumor Stem Cell Assay; Up-Regulation; Xanthones

Gambogic acid (GA) is the major active ingredient of gamboge, a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia. The present study aims to demonstrate that gambogic acid (GA) has potent anticancer activity for glioblastoma by in vitro and in vivo study. Rat brain microvascular endothelial cells (rBMEC) were used as an in vitro model of the blood-brain barrier (BBB). To reveal an involvement of the intrinsic mitochondrial pathway of apoptosis, the mitochondrial membrane potential and the western blot evaluation of Bax, Bcl-2, Caspase-3, caspase-9 and cytochrome c released from mitochondria were performed. Angiogenesis was detected by CD31 immunochemical study. The results showed that the uptake of GA by rBMEC was time-dependent, which indicated that it could pass BBB and represent a possible new target in glioma therapy. GA could cause apoptosis of rat C6 glioma cells in vitro in a concentration-dependent manner by triggering the intrinsic mitochondrial pathway of apoptosis. In vivo study also revealed that i.v. injection of GA once a day for two weeks could significantly reduce tumor volumes by antiangiogenesis and apoptotic induction of glioma cells. Collectively, the current data indicated that GA may be of potential use in treatment of glioblastoma by apoptotic induction and antiangiogenic effects.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Cytochromes c; Glioblastoma; Membrane Potential, Mitochondrial; Rats; Rats, Sprague-Dawley; Tumor Burden; Xanthones