Combination treatment of TRAIL, DFMO and radiation for malignant glioma cells

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancer. Another promising cancer therapy is difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which is oraly administered and well tolerated. Nevertheless, many types of cancer, including gliomas, have exhibited resistance to TRAIL-induced apoptosis and similarly the potency of DFMO should be enhanced to optimize therapeutic efficacy. In this study we sought to determine whether DFMO, in combination with TRAIL and radiation, could result in an enhanced anti-glioma effect in vitro. We investigated the effect of DFMO, TRAIL and radiation in various combinations on a panel of glioblastoma cell lines (A172, T98G, D54, U251MG). Viability and proliferation of the cells were examined with trypan blue exclusion assay, crystal violet and xCELLigence system. Apoptosis (Annexin-PI), cell cycle and activation of caspase-8 were tested with flow cytometry. BAD protein levels were determined by Western blot analysis. DFMO induced BAD overexpression. Combination treatment with DFMO, TRAIL and radiation significantly reduced cell viability in all cell lines tested. Increased induction of cell death and cell cycle arrest was confirmed with flow cytometry in A172 and D54 cell lines, while enhanced activation of annexin and caspase-8 was revealed in U251MG and T98G cells. The treatment of glioblastoma cell lines with combination of DFMO, TRAIL and radiation showed an enhanced effect. This combination treatment may represent a novel strategy for targeting glioblastoma.

Targeting polyamine metabolism for cancer therapy and prevention

“…Although it is too early to predict if such a combination might have clinical utility, it does underscore the continued interest in the clinical development of the well-tolerated ODC inhibitor [64]. …”

Iron(II)−Polypyridyl Complexes Inhibit the Growth of Glioblastoma Tumor and Enhance TRAIL‐Induced Cell Apoptosis

“…For example, suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, in combination with TRAIL was found to be an effective strategy for breast cancer therapy . Difluoromethylornithine, in combination with TRAIL and radiation treatment, increased the therapeutic efficacy of glioblastoma treatments . Carnosic acid efficiently sensitized the TRAIL‐induced apoptosis of caki cells by inhibiting the expression of c‐FLIP (c‐FLIP=FLICE‐like inhibitory protein; FLICE=FADD‐like IL‐1ß‐converting enzyme) and Bcl‐2 (B‐cell lymphoma 2) and inducing the CHOP (C/EBP homologous protein; EBP=emopamil binding protein)‐dependent up‐regulation of DR5, Bim, and PUMA (PUMA=p53 upregulated modulator of apoptosis) expression .…”

“…[10] Difluoromethylornithine, in combination with TRAIL and radiation treatment, increased the therapeutice fficacy of glioblastoma treatments. [11] Carnosic acid efficientlys ensitized the TRAIL-induced apoptosis of caki cells by inhibiting the expression of c-FLIP (c-FLIP = FLICE-like inhibitory protein;F LICE = FADD-like IL-1ß-converting enzyme) and Bcl-2 (B-celll ymphoma2)a nd inducingt he CHOP (C/EBP homologous protein;E BP = emopamil binding protein)-dependentu pregulation of DR5, Bim, and PUMA (PUMA = p53 upregulated modulator of apoptosis) expression. [12] Someother nanocarriers also exhibited promisings ensitizing capacity of TRAIL in chemotherapy against severalT RAIL-resistance cancers.…”

Targeting metabolic vulnerabilities of cancer: Small molecule inhibitors in clinic

“…DFMO undergoes enzymatic decarboxylation, liberating the fluoride ion and binds within the active site at lys 69 and lys 360 of ODC, thereby depleting intracellular polyamine pools (Figure ). The use of DFMO in pre‐clinical settings has been widely examined . In gliomas, DFMO induces dose‐dependent cell‐cycle arrest at G0/G1 phase and intrinsic apoptosis via overexpression of Bax, Bad and reduction of bcl‐2 in vitro .…”