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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.

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Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells

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  1. Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells BACK TO THE BEGINNING

  2. 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.

  3. 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

  4. IUdR+MX + IR Mechanism underlying the enhanced radiosensitization?

  5. MX enhances IUdR-DNA incorporation and potentiates IUdR-induced radiosensitization in RKO cells B A Yan T et al. Mol Cancer Ther 5:893-902, 2006

  6. IUdR/MX pretreatment results in changes in DNA damage signaling following IR Control IUdR IUdR/MX 0 1 3 6 0 1 3 6 0 1 3 6 h post-IR H2AX pChk1(S317) pChk2(T68) β-actin Yan T et al. Mol Cancer Ther 5:893-902, 2006

  7. IUdR/MX pretreatment partially suppresses IR-induced apoptotic cell death (sub-G1) 0 24 48 72 h post-IR 1.9 4.1 14.8 12.1% sub-G1 Control 1.6 3.2 8.9 5.1% sub-G1 IUdR 2.1 3.1 13.8 10.2% sub-G1 MX 3 3.9 7.8 4.4% sub-G1 IUdR/MX PI Yan T et al. Mol Cancer Ther 5:893-902, 2006

  8. IUdR/MX pretreatment partially suppresses IR-induced apoptotic cell death (chromatin condensation and PARP cleavage) A Control IUdR MX IUdR/MX IR 48h IR 72h B Control IUdR IUdR/MX 0 24 48 72 0 24 48 72 0 24 48 72 h post-IR PARP p85 β-actin Yan T et al. Mol Cancer Ther 5:893-902, 2006

  9. IUdR/MX pretreatment appears not to enhance necrotic cell death (PI staining) Control IUdR MX IUdR/MX NT Drugs day 2 IR 24h IR 48h IR 72h Total PI+ 13.3 13.5 12.5 12.4% 0% Yan T et al. Mol Cancer Ther 5:893-902, 2006

  10. IUdR/MX pretreatment appears not to enhance autophagic cell death (LC3-II) Control IUdR IUdR/MX 0 24 48 72 0 24 48 72 0 24 48 72 h post IR LC3-I LC3-II α-tubulin Yan T et al. Mol Cancer Ther 5:893-902, 2006

  11. IUdR/MX pretreatment enhances stress-induced premature senescence following IR A MX- + IUdR - β-gal staining + B IUdR IUdR/MX Crystal violet staining 18.8±2.7% 33.6±4.1% Yan T et al. Mol Cancer Ther 5:893-902, 2006

  12. G1 G2 (high cyclin B1) Cyclin B1 4CG1(low cyclin B1) PI Cellular characteristics of IUdR/MX/IR-induced senescent cells (4CG1 population) Hours after IR 0 24 48 72 Control 0 24 48 72 IUdR 0 24 48 72 IUdR/MX 0 24 48 72 Yan T et al. Mol Cancer Ther 5:893-902, 2006

  13. Hours post-IR 0 24 48 72 96 120 144 168 Control IUdR IUdR/MX 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

  14. Cellular characteristics of IUdR/MX/IR-induced senescent cells (activation of senescence factors) IUdR IUdR/MX 0 24 48 72 0 24 48 72 h post-IR p53 p21 hyper-pRb hypo-pRb pRb (S780) actin Yan T et al. Mol Cancer Ther 5:893-902, 2006

  15. Conclusion MX potentiates IUdR-induced radiosensitization not by enhancing apoptosis, necrosis and autophagic cell death but by enhancing senescence.

  16. 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?

  17. Tumor cell response to DNA damage RECOVERY SENESCENCE CHECKPOINT ARREST MITOTIC CATASTROPHE AUTOPHAGY DNA DAMAGE APOPTOSIS NECROSIS

  18. DNA damage-inducedcell death as a system 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?

  19. Question For the modeling of cell death - What are inputs? - What are outputs that are of predictive nature?

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