Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Aravindan, Natarajan; Veeraraghavan, Jamunarani; Madhusoodhanan, Rakhesh; Herman, Terence S.; Natarajan, Mohan

doi:10.1016/j.ijrobp.2010.10.058

Cited by 41 publications

(35 citation statements)

References 34 publications

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“…Many recently studies show that the telomerase involved in the progress of the DNA DSB repair. And several studies also supports that the telomerase activity and the telomere status have impacts on the response to ionizing radiation (Aravindan et al, 2011). Current literature indicates that telomerase has a radiationinducible function lead to resistance of cells to irradiation.…”

Section: Discussionmentioning

confidence: 89%

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

Chen¹,

Liu²

2012

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 89%

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

Chen¹,

Liu²

2012

Asian Pacific Journal of Cancer Prevention

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“…Recently, we dissected out that IR induced NFκB in human NB cells [14,15] is responsible for the induced TERT transcription, enhanced TA and subsequent clonal expansion [16]. In this context, clearly, there is a need to recognize new, effective and clinical-translation feasible drugs that selectively target radiation induced NFκB-dependent TERT to mitigate clonal expansion and NB progression.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, clearly, there is a need to recognize new, effective and clinical-translation feasible drugs that selectively target radiation induced NFκB-dependent TERT to mitigate clonal expansion and NB progression. Concurrently, we have shown that curcumin (diferuloylmethane), a polyphenol, sensitizes NB cells to the apoptotic effects of radiation [14] and, further mitigates radiation-induced NFκB-dependent TERT transcription, TA and subsequent clonal expansion [16]. However, the full potential of curcumin has not been realized because of the relatively poor bioavailability in the clinical settings [17,18].…”

Section: Introductionmentioning

confidence: 99%

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

et al. 2013

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Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

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“…Our previous work has suggested that IR-induced NFκB in surviving tumor cells is a critical determinant of overall response to RT (5, 6, 14) and further demonstrated that selectively targeting IR-induced NFκB alleviated radiation resistance in many tumor models (8, 9, 11, 17-19). Therefore, targeting the NFκB pathway involved in the secretion of radiation-responsive factors such as SOD2, cMYC, IL-1α or TNF-α may prove a promising strategy to mitigate IR-induced radiation protection.…”

Section: Discussionmentioning

confidence: 96%

Acquired Tumor Cell Radiation Resistance at the Treatment Site Is Mediated Through Radiation-Orchestrated Intercellular Communication

Aravindan

Vijayabaskar

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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Purpose Radiation resistance induced in cancer cells that survive after radiation therapy (RT) could be associated with increased radiation protection, limiting the therapeutic benefit of radiation. Herein we investigated the sequential mechanistic molecular orchestration involved in radiation-induced radiation protection in tumor cells. Results Radiation, both in the low-dose irradiation (LDIR) range (10, 50, or 100 cGy) or at a higher, challenge dose IR (CDIR), 4 Gy, induced dose-dependent and sustained NFκB-DNA binding activity. However, a robust and consistent increase was seen in CDIR-induced NFκB activity, decreased DNA fragmentation, apoptosis, and cytotoxicity and attenuation of CDIR-inhibited clonal expansion when the cells were primed with LDIR prior to challenge dose. Furthermore, NFκB manipulation studies with small interfering RNA (siRNA) silencing or p50/p65 overexpression unveiled the influence of LDIR-activated NFκB in regulating CDIR-induced DNA fragmentation and apoptosis. LDIR significantly increased the transactivation/translation of the radiation-responsive factors tumor necrosis factor-α (TNF- α), interleukin-1 α (IL-1α), cMYC, and SOD2. Coculture experiments exhibit LDIR-influenced radiation protection and increases in cellular expression, secretion, and activation of radiation-responsive molecules in bystander cells. Individual gene-silencing approach with siRNAs coupled with coculture studies showed the influence of LDIR-modulated TNF- α, IL-1α, cMYC, and SOD2 in induced radiation protection in bystander cells. NFκB inhibition/overexpression studies coupled with coculture experiments demonstrated that TNF- α, IL-1 α, cMYC, and SOD2 are selectively regulated by LDIR-induced NFκB. Conclusions Together, these data strongly suggest that scattered LDIR-induced NFκB-dependent TNF-α, IL-1α, cMYC, and SOD2 mediate radiation protection to the subsequent challenge dose in tumor cells.

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Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Cited by 41 publications

References 34 publications

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

Acquired Tumor Cell Radiation Resistance at the Treatment Site Is Mediated Through Radiation-Orchestrated Intercellular Communication

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