Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: Role of reactive oxygen species, GSH and Nrf2 in radiosensitivity

Jayakumar, S.; Kunwar, Amit; Sandur, Santosh K.; Pandey, Badri N.; Chaubey, R.C.

doi:10.1016/j.bbagen.2013.10.006

Cited by 101 publications

(84 citation statements)

References 29 publications

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“…As for radiotherapy, certain levels of ROS in cells are necessary. The manipulation of cellular redox systems by reducing GSH or NADH activity increases radiosensitivity [62,63]. Similar results were also reported in studies focusing on SOD.…”

Section: Controversial Role Of Antioxidants In Combined Treatmentsupporting

confidence: 70%

Reactive oxygen species in redox cancer therapy

et al. 2015

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Section: Controversial Role Of Antioxidants In Combined Treatmentsupporting

confidence: 70%

Reactive oxygen species in redox cancer therapy

et al. 2015

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“…Indeed, a previous study showed that DU145 cells have higher basal GSH levels and a reducing redox environment when compared with other prostate cancer cells, enhancing their tolerability to ROS (Jayakumar et al, 2014). Alternatively, the Dp44mT:Fe and DpC:Fe complexes may have additional molecular effects in this cell line that are not accounted for by ROS production alone.…”

Section: Resultsmentioning

confidence: 99%

Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6–Induced Activation by Iron Depletion

et al. 2015

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Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway.

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“…In this regard, our earlier study involving prostate cancer cell lines, it has been shown that the radio-resistant cell line had higher levels of Nrf2 and lower levels of DNA damage upon irradiation as compared to radio-sensitive cell line [8]. In another study, Kim et al [22] have shown that the expression of 53BP1 (p53 binding protein) was dependent on Nrf2 in normal cells.…”

Section: Introductionmentioning

confidence: 92%

“…Several studies have demonstrated the usefulness of targeting Nrf2 for radiosensitization [8][9][10][11]. Similar to antioxidant response, DNA damage response (DDR) also is an important aspect which determines the radiation response of tumor cells.…”

Section: Introductionmentioning

confidence: 99%