Abstract
Glioblastoma is the most malignant brain tumor of astroglial origin. It renders poor response or resistance to existing therapeutics. We used all-trans retinoic acid (ATRA) and interferon gamma (IFN-γ) alone and in combination for controlling human glioblastoma T98G xenografted in nude mice. Histopathological examination showed astrocytic differentiation in ATRA group, some apoptosis in IFN-γ group, and occurrence of differentiation and enhancement of apoptosis in ATRA plus IFN-γ group. ATRA plus IFN-γ induced extrinsic pathway of apoptosis by activation of caspase-8 and cleavage of Bid to tBid and also down regulation of hTERT, c-IAP2, and survivin and upregulation of Smac/Diablo to promote apoptosis. Mitochondrial release of apoptosis-inducing factor (AIF) induced caspase-independent pathway and also upregulation of calpain and caspase-dependent pathways ultimately activated caspase-3 for apoptosis. Increased activities of calpain and caspase-3 degraded 270 kD α-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. In situ TUNEL and double immunofluorescent labelings detected apoptosis with increased expression of calpain, caspase-12, caspase-3, and AIF in tumors after treatment with IFN-γ and most effectively with ATRA plus IFN-γ. Results indicated that ATRA plus IFN-γ activated multiple molecular mechanisms for increasing apoptosis in human glioblastoma in vivo.
Highlights
Glioblastoma is the most common malignant brain tumor in humans (Rasheed et al, 1999)
Examination of hematoxylin and eosin (H&E) stained tumor sections showed the characteristic feature of glioblastoma in control tumors, all-trans retinoic acid (ATRA) monotherapy inhibited tumor cell proliferation and induced astrocytic differentiation, IFN-γ monotherapy induced moderate apoptosis, and ATRA plus IFN-γ treatment caused substantial amounts of apoptosis in differentiated cells
Western blotting demonstrated that ATRA plus IFN-γ stimulated the receptor-mediated pathway of apoptosis for activation of caspase-8 that caused cleavage of Bid to tBid to trigger mitochondrial intrinsic pathway in T98G xenograft (Figure 2)
Summary
Glioblastoma is the most common malignant brain tumor in humans (Rasheed et al, 1999). Current therapy for glioblastoma includes mass-reductive surgery, radiation, and chemotherapy (Benítez et al, 2008) but it eventually proves to be ineffective due to failure in controlling aggressive cell proliferation and metastatic invasion. Development of innovative therapeutic strategies is highly warranted for treating this deadliest disease. Poor differentiation and uncontrolled cell proliferation in glioblastoma are major problems. These peculiarities should be considered in order to develop a suitable therapeutic regimen for controlling glioblastoma. We used a combination therapy for induction of differentiation and enhancement of apoptosis in human glioblastoma in vivo
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