Preclinical effects of CRLX101, an investigational camptothecin-containing nanoparticle drug conjugate, on treating glioblastoma multiforme via apoptosis and antiangiogenesis

Abstract

Malignant gliomas are difficult to treat in clinical practice. This study was aimed to investigate the preclinical efficacy of CRLX101, an investigational nanoparticle-drug conjugate developed by conjugating camptothecin (CPT) with cyclodextrin-polyethylene glycol, against gliomas. CPT fluorescence was detected across tight-junction barriers and in mouse plasma and brain. Following CRLX101 treatment, CPT was distributed in the cytoplasm of human U87 MG glioma cells. U87 MG cell viability was decreased by CRLX101 and CPT. Moreover, CRLX101 induced less cytotoxicity to human astrocytes compared to CPT. Exposure of U87 MG cells to CRLX101 induced G2/M cell cycle arrest and apoptosis. Administration of CRLX101 induced apoptosis in mice brain tumor tissues and prolonged the survival rate of mice. In addition, CRLX101 inhibited hypoxia and angiogenesis by suppressing the expression of carbonic anhydrase IX, vascular endothelial growth factor, and CD31 in tumor sections. Taken together, this preclinical study showed that CRLX101 possesses antitumor abilities by inducing cell cycle arrest and apoptosis in glioma cells and inhibiting tumor angiogenesis, thereby prolonging the lifespan of mice bearing intracranial gliomas. These data support further research of CRLX101 in patients with brain tumors.

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

“…Human U‐87 MG and GBM8401 cells used in this study were provided by Professor Ruei‐Ming Chen, Taipei Medical University, Taiwan and Professor Jing‐Gung Chung, China Medical University, Taiwan, respectively. Cells were maintained in MEM medium or RPMI‐1640 medium with 10% FBS, 100 IU/mL penicillin, 100 mg/mL streptomycin and 1 mmol/L sodium pyruvate, and then incubated at 37°C in a humidified atmosphere of 5% CO 2 . Cells were grown to 70%‐80% confluence before drug treatment.…”

Amentoflavone Induces Apoptosis and Inhibits NF-ĸBmodulated Anti-apoptotic Signaling in Glioblastoma Cells

“…Human U-87 MG glioblastoma cells were kindly provided by Professor Ruei-Ming Chen, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University and used for this study. Cells were cultured in Minimum Essential Medium Eagle's medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin (10,000 U/ml) and 1% sodium pyruvate (100 mM) at 37˚C in a humidified incubator with 5% CO 2 (10).…”

Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms

“…Breast tumors showed an improved response with a delayed recurrence [119]. In addition, an induced cancer stem cells population was retarded by bevacizumab treatment [119,120]. Clinically, a phase I trial in patients with advanced, refractory malignancies including breast and lung cancers demonstrated that the inhibition of angiogenic activity was achieved by a combination of bortezomib, an agent that inhibits HIF-1α, with a bevacizumab regimen [121].…”