TY - JOUR
T1 - Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma
AU - Dewdney, Brittany
AU - Miranda, Panimaya Jeffreena
AU - Kuchibhotla, Mani
AU - Palanisamy, Ranjith
AU - Richworth, Caitlyn
AU - Milligan, Carol J.
AU - Ng, Zi Ying
AU - Ursich, Lauren
AU - Petrou, Steve
AU - Fletcher, Emily
AU - Daly, Roger J.
AU - Lim Kam Sian, Terry C. C.
AU - Valvi, Santosh
AU - Endersby, Raelene
AU - Johns, Terrance G.
PY - 2024/12/6
Y1 - 2024/12/6
N2 - Background Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.Methods Seventy-two ion channel inhibitors were screened in patient-derived glioblastoma cells, and cell viability was determined using the ViaLight Assay. Cell cycle and apoptosis analysis were determined with flow cytometry using PI and Annexin V staining, respectively. Protein and phosphoprotein expression was determined using mass spectrometry and analyzed using gene set enrichment analysis. Kaplan-Meier survival analyses were performed using intracranial xenograft models of GBM6 and WK1 cells.Results The voltage-gated sodium channel modulator, DPI-201-106, was revealed to reduce glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomics indicated that DPI-201-106 may impact DNA damage response (DDR) pathways. Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice.Conclusions DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.Glioblastoma is an aggressive type of brain cancer. Proteins in cells called ion channels help relay signals between cells and may play a role in cancer growth. The authors of this study wanted to see if blocking ion channels could help treat glioblastoma. To do this, they tested 72 drugs on glioblastoma cells taken from patient tumors. Their results showed that 1 drug, called DPI-201-106, stopped cancer cells from dividing and caused cell death. When they combined this drug with others that caused DNA damage, it worked even better, both in laboratory dishes and in mice with glioblastoma.
AB - Background Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.Methods Seventy-two ion channel inhibitors were screened in patient-derived glioblastoma cells, and cell viability was determined using the ViaLight Assay. Cell cycle and apoptosis analysis were determined with flow cytometry using PI and Annexin V staining, respectively. Protein and phosphoprotein expression was determined using mass spectrometry and analyzed using gene set enrichment analysis. Kaplan-Meier survival analyses were performed using intracranial xenograft models of GBM6 and WK1 cells.Results The voltage-gated sodium channel modulator, DPI-201-106, was revealed to reduce glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomics indicated that DPI-201-106 may impact DNA damage response (DDR) pathways. Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice.Conclusions DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.Glioblastoma is an aggressive type of brain cancer. Proteins in cells called ion channels help relay signals between cells and may play a role in cancer growth. The authors of this study wanted to see if blocking ion channels could help treat glioblastoma. To do this, they tested 72 drugs on glioblastoma cells taken from patient tumors. Their results showed that 1 drug, called DPI-201-106, stopped cancer cells from dividing and caused cell death. When they combined this drug with others that caused DNA damage, it worked even better, both in laboratory dishes and in mice with glioblastoma.
KW - DNA damage
KW - Cell cycle
KW - Glioblastoma
KW - Ion channel
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=uwapure5-25&SrcAuth=WosAPI&KeyUT=WOS:001373223500001&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1093/noajnl/vdae187
DO - 10.1093/noajnl/vdae187
M3 - Article
C2 - 39659830
SN - 2632-2498
VL - 6
JO - Neuro-Oncology Advances
JF - Neuro-Oncology Advances
IS - 1
M1 - vdae187
ER -