Neural Stem Cells and Glioma Stem-Like Cells Respond Differently to Chemotherapeutic Drugs: Selectivity at the Cellular Level

Abstract

Despite recent refinements of current treatment modalities and the discovery of targets for novel drugs, the prognosis of patients with glioblastoma multiforme (GBM) is still dismal. Since temozolomide (TMZ) given concomitantly with and after radiotherapy became the first-line treatment in newly-diagnosed GBMs, patient survival has significantly increased as shown in prospective clinical trials. In their recently published work, Gong et al from UC Irvine School of Medicine, CA (Neurology. 2011;76(13):1126-1134) investigated the molecular and cellular in vitro effects of different chemotherapeutic agents on different neural stem/progenitor cells (NSC) and glioma stem-like cells (GSC). In 3 human NSC and multiple GSC cell lines, the authors showed that NSC are more vulnerable to TMZ and carboplatin (CIP) than GSC (Figure). Classic MGMT expression was similar in all cell lines (NSC and GSC), suggesting that differences in the MGMT expression do not explain the observed differences in TMZ resistance. Likewise, there were no differences between GCS and NSC in the expression of mismatch repair enzymes MLH1 and MLH2, which has been shown to be responsible for resistance to CIP. However, GCS showed a 10 times higher level of ABCG2, which extrudes toxic drugs. In contrast, Gong et al showed that bortezomib (BTZ), a proteasome inhibitor, and Erlotinib (ERL), an EGF tyrosine kinase inhibitor, decreased the viability of GCS while minimally affecting NSC. By measuring the activity of caspase-3, a key enzyme in apoptosis, after BTZ treatment, the authors demonstrated a significant increase in caspase-3 activity in GSC, which was reversed by a caspase-3 inhibitor. This increase was not seen in NSC. Furthermore, NSC had a five to seven times higher proteasome activity than GSC. To explain the increased effects of ERL on GSC, the author showed that GSC had a consistently high expression of the epidermal growth factor receptor (EGFR), while NSC had only low-level expressions. The authors nicely show that classic GBM chemotherapeutic drugs have different in vitro effects on neural stem cells and glioma stem-like cells. Although the clinical setting is more complex than the in vitro environment, the inefficiency of TMZ and CIS in affecting GSC might be a reason for resistance to chemotherapy in human GBM. The most noteworthy message of this study is the need for more selective drugs that destroy the most appropriate target and spare healthy brain tissue.Caption not available.Jan-Karl Burkhardt Benjamin J. Shin John A. Boockvar