Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Published byMorgan Bruce Modified over 8 years ago

Similar presentations

Presentation on theme: "Methoxyamine (MX) potentiates IUdR-induced radiosensitization by enhancing senescence in RKO cells BACK TO THE BEGINNING."— Presentation transcript:

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 Mechanism underlying the enhanced radiosensitization? IUdR + MX + IR

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

6 0 1 3 6 0 1 3 6 0 1 3 6 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 5:893-902, 2006

7 IUdR MX Control IUdR/MX 0 24 48 72 h post-IR 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

8 B 0 24 48 72 0 24 48 72 0 24 48 72 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 5:893-902, 2006

9 Drugs day 2 IR 24h IR 48h IR 72h Control IUdR MX IUdR/MX NT 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

10 0 24 48 72 0 24 48 72 0 24 48 72 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 5:893-902, 2006

11 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 5:893-902, 2006

12 0 24 48 72 Control IUdR 0 24 48 72 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 5:893-902, 2006

13 Control IUdR/MX IUdR 0 24 48 72 96 120 144 168 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

14 p53 p21 actin pRb (S780) hyper-pRb hypo-pRb 0 24 48 72 0 24 48 72 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 5:893-902, 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 DNA DAMAGE CHECKPOINT ARREST RECOVERY SENESCENCE APOPTOSIS NECROSIS AUTOPHAGY Tumor cell response to DNA damage MITOTIC CATASTROPHE

18 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

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

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

Similar presentations

 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.

 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.
2 E Conférence Québécoise Sur La Résistance Thérapeutique du Cancer Q-CROC Montréal, November 5-6, 2010.

2 E Conférence Québécoise Sur La Résistance Thérapeutique du Cancer Q-CROC Montréal, November 5-6, 2010.
P53, Apoptosis, Cancer, More Regulation G1 checkpoint Controlled by G1 Cdk-cyclin G1 cyclin levels also vary with the cell cycle Many additional levels.

P53, Apoptosis, Cancer, More Regulation G1 checkpoint Controlled by G1 Cdk-cyclin G1 cyclin levels also vary with the cell cycle Many additional levels.
Mechanisms of DNA damage-Induced Cell Death Radiobiology 2012.

Mechanisms of DNA damage-Induced Cell Death Radiobiology 2012.
DNA Repair. Cell Cycle Checkpoint activation DNA Repair: Base Excision Repair Nucleotide excision repair Mismatch repair DSB repair SENESCENCE / APOPTOSIS.

DNA Repair. Cell Cycle Checkpoint activation DNA Repair: Base Excision Repair Nucleotide excision repair Mismatch repair DSB repair SENESCENCE / APOPTOSIS.
Characterization of a potential new drug in cancer therapy Lab 2 Salah Farag.

Characterization of a potential new drug in cancer therapy Lab 2 Salah Farag.
APOPTOSIS “Cell Death” By Brian Abadie, Emily Anderson, andJohn Ramsey.

APOPTOSIS “Cell Death” By Brian Abadie, Emily Anderson, andJohn Ramsey.
When mammalian cells are subjected to stress signals, oxygen deficiency, radiation, DNA damage, or Chemo- therapeutic drugs, p53 is activated, leading.

When mammalian cells are subjected to stress signals, oxygen deficiency, radiation, DNA damage, or Chemo- therapeutic drugs, p53 is activated, leading.
Programmed Cell death Saeb Aliwaini April/2013. Introduction Human Body makes 10 billion cells every day. Cell death makes balance : There are various.

Programmed Cell death Saeb Aliwaini April/2013. Introduction Human Body makes 10 billion cells every day. Cell death makes balance : There are various.
Figure S1 A MRC5 Control Chk1 TdR(h): γH2AX Cleaved casp3 RPA34

Figure S1 A MRC5 Control Chk1 TdR(h): γH2AX Cleaved casp3 RPA34
Lecture 11: Cell proliferation, differentiation, and death Dr. Mamoun Ahram Faculty of Medicine Second year, Second semester, 2014-2014 Principles of.

Lecture 11: Cell proliferation, differentiation, and death Dr. Mamoun Ahram Faculty of Medicine Second year, Second semester, Principles of.
Signaling Pathways Produced By Combining DsRNA with Paclitaxal to treat Ovarian Cancer Switu Patel.

Signaling Pathways Produced By Combining DsRNA with Paclitaxal to treat Ovarian Cancer Switu Patel.
Cellular Senescence: A Link between Tumor Suppression and Organismal Aging.

Cellular Senescence: A Link between Tumor Suppression and Organismal Aging.
 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.

 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.
Lecture #3 The Cell Cycle & Cancer

Lecture #3 The Cell Cycle & Cancer
1 H2AX: functional roles and potential applications.

1 H2AX: functional roles and potential applications.
Apoptosis (Programmed Cell Death). Apoptosis vs Necrosis Level of stress, change in environment stress apoptosisnecrosis.

Apoptosis (Programmed Cell Death). Apoptosis vs Necrosis Level of stress, change in environment stress apoptosisnecrosis.
Regulating the Cell Cycle

Regulating the Cell Cycle
1 Dr. Karen Schmeichel February 3, 2009 BIO 290 Special Topics in Biology: Cancer Biology Lecture #7 Finishing “Profiling” & “Models Of Cancer”

1 Dr. Karen Schmeichel February 3, 2009 BIO 290 Special Topics in Biology: Cancer Biology Lecture #7 Finishing “Profiling” & “Models Of Cancer”
 Cell cycle is known, so now we ask what controls it  We have observed many factors that influence a cell’s ability to move forward in the cycle ◦ Kinetochores.

 Cell cycle is known, so now we ask what controls it  We have observed many factors that influence a cell’s ability to move forward in the cycle ◦ Kinetochores.

Similar presentations

Ads by Google