Dipg-62. Carboplatin Synergizes With Bcl-2 Inhibitor to Potentiate Killing of Dipg Cells
Year: 2018
Type: conference-abstract
Abstract: The only proven effective therapy for diffuse intrinsic pontine glioma is radiation, and this modality only extends life. Carboplatin is being explored for convection-enhanced delivery in DIPG patients, with the hypothesis being that high doses of carboplatin can effectively kill DIPG cells. The BH3-mimetic, pro-apoptotic drug Obatoclax has excellent brain penetration, making it an appropriate candidate for DIPG therapy. We hypothesized that Carboplatin and Obatoclax would synergize to increase killing of DIPG cells. Carboplatin causes cell death via DNA interchelation. Obatoclax induces apoptosis by inhibition of BCL-2 family of proteins. We found that each drug was effective at low micro-molar to nano-molar doses in JHH-DIPG1, SF7761, SU-DIPG-13 and JHH-DIPG16A cell lines. SF7761 and JHH-DIPG16A are derived from pre-treatment biopsies while SUDIPG13 and JHH-DIPG1 are derived from autopsy samples. We found IC50 of Carboplatin to be 5uM and Obatoclax to be 1nM respectively in our cell lines. Combination therapy by these two drugs led to: (1) decreased BCL-2 expression in all 4 cell lines; (2) decreased proliferation as measured by BrdU (ANOVA p value: 0.0004); (3) threefold increase in cleaved PARP as measured by western blot within 24 hours of incubation in all cell lines. We used immunofluorescence to measure cleaved caspase 3 and found 50 percent increase in this marker of apoptosis as well (p<0.01) via combination therapy. Due to the promising synergistic effects in multiple DIPG cell lines in vitro, tests of efficacy in vivo using DIPG cell lines are currently underway.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2809116239