Untitled

Abstract

Glioblastoma multiforme (WHO grade IV; GBM) is the most common primary brain tumor with a median survival of less than one year despite multimodal treatment regimens. However, a small subgroup of GBM patients has a better clinical outcome, with a small number of patients surviving several years. Apoptosis, a genetically determined program of cell suicide, may be induced as a consequence of critical DNA damage. However, due to defects in the signaling pathways, cancer cells may escape apoptosis, despite carrying irreversible DNA damage. In the present study, we have analyzed tumors of two age-matched, equally treated groups of GBM patients with different postoperative time to tumor progression (TTP), defined as 'short-term' for TTP of less than 6 months (n = 54), and 'long-term' for TTP of more than 12 months (n = 39) for alterations in apoptosis regulatory pathways: Mutations of the TP53 tumor suppressor gene and/or nuclear accumulation of its gene product p53, expression of Waf/p21, CD95 (Apo1/Fas), and Bcl-2. TP53 mutations were found in 12 out of 54 (22%) GBMs of short-term survivors and 8 out of 35 (23%) tumors of long-term survivors; the respective numbers for nuclear p53 protein accumulation were 12/53 (23%) and 10/37 (27%). Waf1/p21 expression was found in 13/53 (25%) tumors of short-term survivors and 9/35 (26%) GBMs of long-term survivors. The respective numbers for Bcl-2 expression were 25/42 (60%) and 22/36 (61%) and for CD95 (Apo1/Fas) expression 20/49 (41%) and 14/36 (39%) GBMs. The percentage of alterations in genes/proteins involved in the apoptotic pathway investigated here was virtually identical in the two groups of clinically different GBM patients. Thus, our data imply that none of these alterations investigated per se has a strong impact on the overall survival of GBM patients.

The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells

“…The present study emphasizes the efficacy of the Bcl-2 family pathway inhibition by Obatoclax in sensitizing patient-derived GSC cultures to HDACi/RTx, and hereby provides a circumvention for a tumor-related resistance mechanism to treatment. The Bcl-2 family proteins are heterogeneously expressed in glioblastoma as about 30%[ 23 ] to 60%[ 24 ] shows over-representation of these proteins. [ 24 - 26 ] Moreover, Bcl-XL levels in patient-derived GSC cultures have shown a relationship with resistance to HDACi/RTx response.…”

“…The Bcl-2 family proteins are heterogeneously expressed in glioblastoma as about 30%[ 23 ] to 60%[ 24 ] shows over-representation of these proteins. [ 24 - 26 ] Moreover, Bcl-XL levels in patient-derived GSC cultures have shown a relationship with resistance to HDACi/RTx response. [ 8 ] Here, we demonstrate that Obatoclax acted synergistically with HDACi and show efficacy in a large set of patient-derived glioblastoma cultures.…”

Integrins and p53 pathways in glioblastoma resistance to temozolomide

“…Data illustrating an association of p53 with survival always point to a longer survival when p53 is mutated (Tada et al, 1998; Schiebe et al, 2000; Birner et al, 2002; Burton et al, 2002). However, the majority of studies do not validate p53 as an independent prognostic marker for glioblastoma (Kraus et al, 2001; Simmons et al, 2001; Shiraishi et al, 2002; Rich et al, 2005; Ruano et al, 2009; Weller et al, 2009; Levidou et al, 2010; Rossi et al, 2011). Overall it means that the prognostic impact of p53 aberrations is only marginal when considered in a global glioblastoma patient population.…”

Anaplastic astrocytomas

“…An inherent problem in the accurate grading of astrocytomas, however, is the marked degree of tumor heterogeneity, namely the presence of areas with varied histological features within the same tumor (Scott et al, 1995). Additionally, AAs can be confused with mixed oligodendroglial tumors because of similarities between the morphological appearances of these two tumors (Kraus et al, 2000). Additionally, AAs can be confused with mixed oligodendroglial tumors because of similarities between the morphological appearances of these two tumors (Kraus et al, 2000).…”