Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells

Haro, Kurtis J.; Scott, Andrew; Scheinberg, David A.

doi:10.1182/blood-2012-01-404509

Cited by 29 publications

(20 citation statements)

References 36 publications

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“…A previous study showed that Rad51 is a HR-specific protein, and high levels of Rad51 enhance resistance to DNA damage [35]. In addition, Rad51-mediated HR is necessary for cell survival in the radioresistance of HL60 cells [36], and downregulation of Rad51 expression may overcome radiation resistance. Here, we also found that both the drug-resistant subline HL60/ADR and radioresistant subline HL60/RX overexpressed the DNA repair pathway protein Rad51 after irradiation, suggesting that the increased ability to repair DNA lesions is a characteristic of radiation resistance in leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Chen

Zhu

et al. 2016

Oncotarget

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Total body irradiation combined with chemotherapy is currently the most effective procedure as a preparative myeloablative regimen. However, resistance to radiotherapy and chemotherapy in refractory acute myeloid leukemia is associated with short-time recurrence after allogeneic hematopoietic stem cell transplantation. To address this issue, we used three cell lines, HL60, HL60/ADR (adriamycin-resistant cells), and HL60/RX (a radiation-resistant cell line established from HL60 cells), as cellular models to investigate the mechanism of the Hedgehog (Hh) signaling pathway resulting in radioresistance, and the efficacy of LDE225 (an inhibitor of the Hh pathway) to enhance radiation sensitivity. Our results indicated that HL60/RX and HL60/ADR cells showed an increased in radioresistance and elevated activity of Hh pathway proteins compared with HL60 cells (P<0.001). In addition, LDE225 significantly reduced clonogenic survival with a sensitivity enhancement ratio (SER) of 1.283 for HL60/ADR and 1.245 for HL60/RX cells. The combination of LDE225 with irradiation significantly increased radiation-induced apoptosis and expression of γ-H2AX and BAK compared with single-treatment groups in both HL60/RX and HL60/ADR cells (P<0.001). In vivo, the combination of LDE225 with irradiation exerted a significant antitumor effect compared with the control and single agents in HL60/RX- and HL60/ADR-xenografted mouse models (P<0.001). Furthermore, our data obtained from western blot and IHC analyses showed that the activation of pAKT and NF-kB was reduced by LDE225 treatment in both HL60/ADR and HL60/RX cells. This demonstrates that the Gli-1/PI3K/AKT/NF-kB pathway plays a key role in resistance to radiation, and that inhibition of the Hh pathway sensitizes cells to radiation by overcoming radioresistance.

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Section: Discussionmentioning

confidence: 99%

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Chen

Zhu

et al. 2016

Oncotarget

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“…Lastly, while generally accepted that there is no effective resistance to α-particle lethality and no oxygen or hypoxia limitations to efficacy making such therapies extremely potent in the therapeutic arenas, Haro et al provides a study on induced resistant clones of HL60 cells to high-LET radiation. While this study was not TAT per se with the α-emission originating from an 241 Am source, it demonstrated that it is possible to have a population of tumor cells that might be refractory to TAT (26). Regardless of these attributes, there have been a very limited number of clinical trials executed to date evaluating TAT (Table 1).…”

Section: Clinical-translational Advancesmentioning

confidence: 93%

Molecular Pathways: Targeted α-Particle Radiation Therapy

Baidoo

Yong

Brechbiel

2013

Clinical Cancer Research

172

127

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An α-particle, a 4He nucleus, is exquisitely cytotoxic, and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α radiation, the result of its high mean energy deposition (high linear energy transfer, LET) and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells (targeted α-therapy (TAT)) with minimal normal tissue effects. There is a burgeoning interest in the development of TAT that is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high-LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double strand (ds) DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly impact cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as 225Ac, 211At, 213Bi, 212Pb and 223Ra.

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“…Earlier studies indicated that low linear energy transfer IR, such as X-rays and γ-rays, induce p53-dependent apoptosis in both normal and cancer cells, whereas high linear energy transfer IR (α-particles) mostly induce p53-independent apoptotic pathway (Haro et al, 2012; Mori et al, 2009). For HIV-infected cells, both X-ray and γ-IR have been shown to induce cell death via chromatin DNA-damage (Ogawa et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

et al. 2015

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The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4+ T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells.

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Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells

Cited by 29 publications

References 36 publications

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Molecular Pathways: Targeted α-Particle Radiation Therapy

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

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