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. ● 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

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

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

IUdR MX Control IUdR/MX h post-IR % sub-G % sub-G % sub-G % sub-G1 IUdR/MX pretreatment partially suppresses IR-induced apoptotic cell death (sub-G1) Yan T et al. Mol Cancer Ther 5: , 2006 PI

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

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

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

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

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

Control IUdR/MX IUdR 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: , 2006

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