Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy

Chinnaiyan, Arul M.; Prasad, Uttara; Hamstra, Daniel A.; Shanaiah, Murthy; Chenevert, Thomas L.; Ross, Brian D.; Rehemtulla, Alnawaz

doi:10.1073/pnas.030545097

Cited by 478 publications

(343 citation statements)

References 41 publications

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“…The most commonly described mechanism of sensitization to TRAIL by drugs and irradiation is up-regulation of TRAIL-R2 and, less commonly, TRAIL -R1. 8,9,16,29,36,39 This mechanism is not operative in the cooperation between TRAIL and TK /GCV in the SH -EP cells studied because no up -regulation was observed following TK /GCV. TRAIL -R2 is a target gene of p53; 41,52 thus, p53 mutations may abrogate up -regulation of TRAIL -R2 following TK /GCV.…”

Section: Discussionmentioning

confidence: 99%

“…8,16 SH -EP cells express little TRAIL -R1, but abundant TRAIL -R2, on the cell surface ( data not shown ). However, cell surface expression of TRAIL-R1 and TRAIL -R2 was not induced following TK / GCV (data Cancer Gene Therapy TRAIL enhances TK/GCV gene therapy of neuroblastoma C Beltinger et al Cancer Gene Therapy TRAIL enhances TK/GCV gene therapy of neuroblastoma C Beltinger et al not shown ).…”

Section: Tk / Gcv Does Not Increase Trail -R1 and Trail -R2mentioning

confidence: 91%

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TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

et al. 2002

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The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death -inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase / ganciclovir ( TK / GCV ) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH -EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK / GCV -induced cell death and decreased clonogenicity of TK -expressing cells and also of bystander cells. Cooperation between TRAIL and TK / GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad -spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl -2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up -regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK / GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK / GCV may explain the cooperative effect of TK / GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK / GCV gene therapy of neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Section: Tk / Gcv Does Not Increase Trail -R1 and Trail -R2mentioning

confidence: 91%

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

et al. 2002

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“…To overcome this resistance, TRAIL-induced signaling is being studied alone or in combination with different sensitizing agents, such as chemotherapeutic drugs, cytokines and inhibitors of survival pathways [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

García-García¹,

Fumarola²,

Navaratnam³

et al. 2010

Biochemical Pharmacology

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMPactivated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP.Here we report that a number of AMPK activators, including the small molecule activator A-769662, markedly sensitize TRAIL-resistant breast cancer cells to TRAIL-induced apoptosis.However, silencing AMPKα1 expression with siRNA or over-expression of DN-AMPKα1 does not inhibit AICAR, glucose deprivation, phenformin or A-769662-induced sensitization to TRAIL. Furthermore, the expression of constitutively active AMPK subunits does not sensitize resistant breast cancer cells to TRAIL-induced apoptosis. The cellular FLICEinhibitory proteins (cFLIP L and cFLIP S ) were significantly down-regulated following exposure to AMPK activators through an AMPK-independent mechanism. Furthermore, in cells over-expressing cFLIP L , sensitization to TRAIL by AMPK activators was markedly reduced. In summary, our results indicate that AMPK activators facilitate the activation by TRAIL of an apoptotic cell death program through a mechanism independent of AMPK and dependent on the down-regulation of cFLIP levels.

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“…Targeting TRAIL-receptor mediated signaling pathways for induction of apoptosis is currently under evaluation in multiple clinical trials for several types of cancer [7,8]. Finally, combined modality treatments, which include γ-irradiation and specific inhibitions of the cell survival pathways, appear to be promising approaches for the control and suppression of cancer development [9,10].…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival

2008

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The incidence of melanoma continues to dramatically increase in most Western countries with predominantly Caucasian populations. However, only limited therapies for the metastatic stage of the disease are currently available. The main purpose of this study is to determine approaches that can substantially increase radiosensitivity of melanoma cells. The PI3K-AKT, NF-κB and COX-2 pathways, which are involved in the radioprotective response, are highly active in melanoma cells. Pharmacological suppression of COX-2 and PI3K-AKT, or RNAi-mediated knockdown of COX-2, substantially increased levels of G2/M arrest of the cell cycle and decreased clonogenic survival of gamma-irradiated melanomas, predominantly via a necrotic mechanism. On the other hand, resveratrol, a polyphenolic phytoalexin, selectively targets numerous cell signaling pathways, decreasing clonogenic survival primarily via an apoptotic mechanism. In melanoma cells, resveratrol inhibits STAT3 and NF-κB-dependent transcription, culminating in suppression of cFLIP and Bcl-xL expression, while activating the MAPK-and the ATM-Chk2-p53 pathways. Resveratrol also upregulates TRAIL promoter activity and induces TRAIL surface expression in some melanoma cell lines, resulting in a rapid development of apoptosis. Sequential treatment of melanoma cells, first with γ-irradiation to upregulate TRAIL-R surface expression, and then with resveratrol to suppress antiapoptotic proteins cFLIP and Bcl-xL and induce TRAIL surface expression, had dramatic effects on upregulation of apoptosis in some melanoma lines, including SW1 and WM35. However, for melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface, a necrotic mechanism of cell death was primarily involved in radiation response. Hence, surface expression of TRAIL induced by resveratrol appears to be a decisive event, one HHS Public Access

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Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy

Cited by 478 publications

References 41 publications

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival

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