Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells
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Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells BACK TO THE BEGINNING
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Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells BACK TO THE BEGINNING. Where we began ● Radiation therapy is a major treatment component in the curative management of most human solid tumors. - PowerPoint PPT Presentation
Transcript of Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells
Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in
RKO cells
BACK TO THE BEGINNING
Where we began
● Radiation therapy is a major treatment component in the curative management of most human solid tumors.
● Enhancing tumor cell radiosensitivity to achieve better therapeutic gain in cancer treatment has been the ultimate goal in our group.
● IUdR radiosensitization has been in Dr. Kinsella’s research interest during the past twenty years.
Where we are
Exploring new adjuvant chemoradiotherapy strategies
• IUdR + IR: enhancing IR-induced DNA double strand breaks
• IUdR + MX + IR: DNA BER repair interference
• IUdR + caffeine/UCN01 + IR: DNA damage G2 checkpoint interference
• IUdR + HDAC inhibitor + IR: chromatin modification interference
Mechanism underlying the enhanced radiosensitization?
IUdR + MX + IR
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MX enhances IUdR-DNA incorporation and potentiates IUdR-induced radiosensitization in RKO cells
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Yan T et al. Mol Cancer Ther 5:893-902, 2006
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H2AX
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IUdR/MX pretreatment results in changes in DNA damage signaling following IR
Yan T et al. Mol Cancer Ther 5:893-902, 2006
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1.9 4.1 14.8 12.1% sub-G1
1.6 3.2 8.9 5.1% sub-G1
2.1 3.1 13.8 10.2% sub-G1
3 3.9 7.8 4.4% sub-G1
IUdR/MX pretreatment partially suppresses IR-induced apoptotic cell death (sub-G1)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
PI
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PARP p85 β-actin
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IUdR/MX pretreatment partially suppresses IR-induced apoptotic cell death (chromatin condensation and PARP cleavage)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
Drugs day 2
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Total PI+ 13.3 13.5 12.5 12.4% 0%
IUdR/MX pretreatment appears not to enhance necrotic cell death (PI staining)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
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IUdR/MX pretreatment appears not to enhance autophagic cell death (LC3-II)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
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IUdR/MX pretreatment enhances stress-induced premature senescence following IR
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Crystal violet staining
Yan T et al. Mol Cancer Ther 5:893-902, 2006
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Cellular characteristics of IUdR/MX/IR-induced senescent cells (4CG1 population)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
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Hours post-IR
Forward Scatter
Cellular characteristics of IUdR/MX/IR-induced senescent cells (enlarged cell size)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
p53
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pRb (S780)
hyper-pRbhypo-pRb
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Cellular characteristics of IUdR/MX/IR-induced senescent cells (activation of senescence factors)
Yan T et al. Mol Cancer Ther 5:893-902, 2006
Conclusion
MX potentiates IUdR-induced radiosensitization not by enhancing apoptosis, necrosis and autophagic
cell death but by enhancing senescence.
Successful chemotherapy and radiotherapy depend on their ability to trigger tumor cell death
Question
● Can we predict the therapeutic efficacy of a cancer treatment strategy using In silico modeling studies?
● Should we model one specific cell death pathway or model all cell death pathways as one entity?
DNA DAMAGE
CHECKPOINT ARREST
RECOVERY
SENESCENCE
APOPTOSIS
NECROSIS
AUTOPHAGY
Tumor cell response to DNA damage
MITOTIC CATASTROPHE
Complex system
Random DNA damages
Cell intrinsic characteristics
Different types of cell death
Overlap
Interdependence
Crosstalk
Shared events Continuum of events
Many events are not controlled in transcription level
Complex regulation network
Simple system
Binary cellular decision
• LIVE/DIE
• GO/STOP
• ON/OFF
What is the switch?
What is the threshold?
DNA damage-induced cell death as a system
Question
For the modeling of cell death
- What are inputs?
- What are outputs that are of predictive nature?
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