Differential Effects of Alpha-Particle Radiation and X-Irradiation on Genes Associated with Apoptosis

Chauhan, Vinita; Howland, Matthew; Chen, Jeremy W; Kutzner, B. C.; Wilkins, Russell

doi:10.1155/2011/679806

Cited by 17 publications

(16 citation statements)

References 29 publications

(32 reference statements)

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“…A recent study from this laboratory demonstrated that the reduction of cell proliferation elicited by the α-emitting radioimmunotherapeutic, 212 Pb-TCMC-trastuzumab, is associated with G2/M arrest, blockage of double-strand DNA damage repair and increased apoptosis 5 . To date, gene modulations associated with α-particle radioimmunotherapy (RIT) have not been defined 9 , 10 . Therefore, to better understand the molecular basis of α-particle RIT, the changes in gene expression in response to α-emitter RIT were investigated.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

et al. 2013

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Recent studies have demonstrated that therapy with 212Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of 212Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to 212Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to 212Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by 212Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by 212Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by 212Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters.The apoptotic response and associated gene modulations have not been clearly defined following exposure of cells to α-particle radioimmunotherapy (RIT). Gene expression profiling was performed with LS-174T i.p. (intraperitoneal) xenografts after exposure to 212Pb-TCMC-trastuzumab. Differentially regulated 22 genes were identified following the stressful growth arrest conditions provoked by 212Pb-TCMC-trastuzumab, providing an informative approach toward understanding the molecular basis of tumor biology in response to α-particle radiation and leading to improved strategies for RIT using α-particle emitters. This study provides data which is among the first to describe in detail, the cellular response to α-particle irradiation in vivo.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

et al. 2013

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“…For example, Chauhan et al [176] detected the expression of Fas and TNF-a in human monocytic THP-1 cells after the cells were irradiated with alpha particles and X-rays with mean absorbed doses from 0 to 1.5 Gy; however, the expression levels of TNF-a were significantly higher for a-particle irradiation. TNF-a could activate the NF-jB/COX-2 signal pathway to induce inflammation-type effect in bystander cells, whereas cyclooxygense-2 (COX-2) was identified as a ''central component'' of RIBE [74] To cite another example, Anzenberg et al [177] found LET-dependent differences in the signal that was released from DU-145 human prostate carcinoma cells by irradiating these cells with alpha particles or 250 kVp X-rays.…”

Section: Studies On High-let-radiation Induced Non-targeted Effectsmentioning

confidence: 99%

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

Choi

2015

Cancer Letters

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“…Despite a long history of studies regarding the mechanisms of action of paclitaxel and photon radiation used individually, little is understood about how paclitaxel and radiation together promote in vivo tumor cell death. In particular, gene modulations associated with the cytocidal response have not been clearly defined following exposure of cells to α-particle RIT combined with paclitaxel [13] , [14] . A recent report from this laboratory showed that paclitaxel potentiates 212 Pb-trastuzumab cytotoxicity, in part, by perturbing the mitotic spindle checkpoint [15] .…”

Section: Introductionmentioning

confidence: 99%

Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

et al. 2014

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To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and 212Pb-trastuzumab (Pac/212Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/212Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/212Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that 212Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.

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Differential Effects of Alpha-Particle Radiation and X-Irradiation on Genes Associated with Apoptosis

Cited by 17 publications

References 29 publications

Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

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Differential Effects of Alpha-Particle Radiation and X-Irradiation on Genes Associated with Apoptosis

Cited by 17 publications

References 29 publications

Gene expression profiling upon 212Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

Gene expression profiling upon 212Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

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Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model

Gene expression profiling upon ²¹²Pb‐TCMC‐trastuzumab treatment in the LS‐174T i.p. xenograft model