The Gene Expression Profiles of Medulloblastoma Cell Lines Resistant to Preactivated Cyclophosphamide

Abstract

The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.

Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing Enzyme

“…Several studies have associated ALDH1B1 with functions other than acetaldehyde metabolism. A recent microarray study showed that ALDH1B1 was up-regulated in medulloblastoma cell lines resistant to cyclophosphamide, suggesting a possible role of ALDH1B1 enzyme in cancer drug resistance (Bacolod et al, 2008). Another study reported that the dynamic expression of ALDH1B1 correlated with granulocytic development of hematopoietic stem cells; in this report, the author proposed a possible role of ALDH1B1 in retinoic acid metabolism mediating the effect (Luo et al, 2007).…”

The PI3K inhibitor GDC-0941 displays promisingin vitro and in vivoefficacy for targeted medulloblastoma therapy

“…Only in D341 previously shown to be resistant to selected cytotoxic drugs 5 μM GDC-0941 were required to achieve this level of suppression [36, 37]. We based our choice of in vitro drug concentrations on the original publication characterizing GDC-0941 as a potent and selective inhibitor of class I PI3K kinase.…”

Gene expression profiling predicts response to temozolomide in malignant gliomas

“…First, it can always be viewed that the expression profiles of cell lines which have undergone many passages do not exactly represent the genetic events that occur in actual tumors (48). Second, the present study was restricted to the use of only seven glioma cell lines.…”