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Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide
Author(s) -
JaimeRamirez Alena Cristina,
Dmitrieva Nina,
Yoo Ji Young,
BanasavadiSiddegowda Yeshavanth,
Zhang Jianying,
Relation Theresa,
Bolyard Chelsea,
Wojton Jeffrey,
Kaur Balveen
Publication year - 2017
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2942
Subject(s) - temozolomide , glioma , oncolytic virus , cancer research , neurosphere , cell growth , chondroitin sulfate , cell culture , chondroitin sulfate proteoglycan , cell , chemistry , biology , in vitro , glycosaminoglycan , biochemistry , endothelial stem cell , genetics , adult stem cell , tumor cells
Background Malignant gliomas (glioblastomas; GBMs) are extremely aggressive and have a median survival of approximately 15 months. Current treatment modalities, which include surgical resection, radiation and chemotherapy, have done little to prolong the lives of GBM patients. Chondroitin sulfate proteoglycans (CSPG) are critical for cell–cell and cell–extracellular matrix (ECM) interactions and are implicated in glioma growth and invasion. Chondroitinase (Chase) ABC is a bacterial enzyme that cleaves chondroitin sulfate disaccharide chains from CSPGs in the tumor ECM. Wild‐type Chase ABC has limited stability and/or activity in mammalian cells; therefore, we created a mutant humanized version (Chase M) with enhanced function in mammalian cells. Methods We hypothesized that disruption of cell–cell and cell–ECM interactions by ChaseM and temozolomide (TMZ) will enhance the chemotherapeutic availability and sensitivity of glioma cells. Results Utilizing primary patient‐derived neurospheres, we found that ChaseM decreases glioma neurosphere aggregation in vitro . Furthermore, an oncolytic HSV‐1 virus expressing secreted ChaseM (OV‐ChaseM) enhanced viral spread and glioma cell killing compared to OV‐Control, in vitro . OV‐ChaseM plus TMZ combinatorial treatment resulted in a significant synergistic enhancement of glioma cell killing accompanied by an increase in apoptotic cell death. Intracellular flow cytometric analysis revealed a significant reduction in the phosphorylation of the pro‐survival AKT protein following OV‐ChaseM plus TMZ treatment. Lastly, in nude mice bearing intracranial GBM30 glioma xenografts, intratumoral OV‐ChaseM plus TMZ (10 mg/kg by oral gavage) combination therapy resulted in a significant ( p < 0.02) enhancement of survival compared to each individual treatment alone. Conclusions These data reveal that OV‐ChaseM enhances glioma cell viral susceptibility and sensitivity to TMZ.