scholarly journals Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption

Oncotarget ◽  
2016 ◽  
Vol 7 (51) ◽  
pp. 85515-85528 ◽  
Author(s):  
Haijun Zhao ◽  
Pengcheng Shi ◽  
Manman Deng ◽  
Zhiwu Jiang ◽  
Yin Li ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Reactive Oxygen Species Generation ◽  
Leukemia Cells ◽  
Oxygen Species ◽  
Damage Response ◽  
Adult Acute Lymphoblastic Leukemia

scholarly journals Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation

2014 ◽  
Vol 21 (6) ◽  
pp. 998-1012 ◽  
Author(s):  
M Ogrunc ◽  
R Di Micco ◽  
M Liontos ◽  
L Bombardelli ◽  
M Mione ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Damage Response ◽  
Response Activation

scholarly journals Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth

2021 ◽  
Vol 22 (4) ◽  
pp. 2088
Author(s):  
Rosalin Mishra ◽  
Long Yuan ◽  
Hima Patel ◽  
Aniruddha S. Karve ◽  
Haizhou Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Cell Growth ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cancer Cell Growth ◽  
Damage Response

RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored. Cell viability of RIDR-PI-103 was assessed on breast cancer cells (MDA-MB-231, MDA-MB-361 and MDA-MB-453), non-tumorigenic MCF10A and fibroblasts. Matrigel colony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR-PI-103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR-PI-103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T1/2 of RIDR-PI-103. MDA-MB-453, MDA-MB-231 and MDA-MB-361 cells were sensitive to RIDR-PI-103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR-PI-103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR-PI-103 inhibited p-AktS473, upregulated p-CHK1/2 and p-P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR-PI-103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T1/2. (4) The prodrug RIDR-PI-103 could be a potential therapeutic for treatment of breast cancer patients.

scholarly journals Robust DNA Damage Response and Elevated Reactive Oxygen Species in TINF2-Mutated Dyskeratosis Congenita Cells

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0148793 ◽  
Author(s):  
Larisa Pereboeva ◽  
Meredith Hubbard ◽  
Frederick D. Goldman ◽  
Erik R. Westin
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Reactive Oxygen ◽  
Dyskeratosis Congenita ◽  
Oxygen Species ◽  
Damage Response

SETD2 Heterozygous Loss in Leukemia Leads to Chemotherapy Resistance through Attenuation of the DNA Damage Response

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2626-2626
Author(s):  
Brenton G. Mar ◽  
Josephine Kahn ◽  
Rebecca L Zon ◽  
Peter V Grauman ◽  
Kevin Boettger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chemotherapy Resistance ◽  
Leukemia Cells ◽  
Protein Synthesis Inhibitor ◽  
Apoptotic Response ◽  
Response To Chemotherapy ◽  
Damage Response

Abstract Relapsed leukemia is chemotherapy resistant and survival is poor. We recently found that mutations in epigenetic regulators are enriched in relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL), suggesting that they are associated with clonal survival and chemotherapy resistance. The mutations included loss of function mutations in the epigenetic regulator SETD2, which had not before been described in B-ALL. SETD2 is the only known mammalian Histone 3 Lysine 36 (H3K36) trimethyltransferase and one or two copy loss leads to a global decrease or elimination, respectively, of its chromatin mark, H3K36me3. Using CRISPR/Cas9 to engineer isogenic human and murine leukemia cells, we have demonstrated that SETD2 loss leads to resistance to DNA damaging chemotherapy used in standard ALL therapy, consistent with the gain of SETD2 mutations at relapse. Leukemia cells with SETD2 heterozygous deletion demonstrated a significant increase in IC50 to the DNA damaging anti-metabolites 6-thioguanine (6TG) and cytarabine (AraC), but not the protein synthesis inhibitor L-Asparaginase (Asp). To model the enrichment of SETD2 mutations at relapse, we competed a small population of SETD2 heterozygous cells with isogenic control leukemia cells. Within 3 weeks, treatment with 6TG and AraC, but not Asp or vehicle, led to a dramatic selection of SETD2 heterozygous cells, mimicking the selective pressure of SETD2 clones in patients. Recent reports have shown that H3K36me3is important in the DNA damage response (DDR). Consistent with this, we find that heterozygous SETD2 loss impairs the DDR signaling pathway with attenuated phosphorylation of multiple DDR components, including Chk1 and Chk2, in response to chemotherapy. Consequently, SETD2 heterozygous cells showed an abrogation of the apoptotic response to the DNA damaging chemotherapy agents 6TG and AraC, despite a normal apoptotic response to Asp. In summary, we have demonstrated that SETD2 loss leads to resistance to DNA damaging chemotherapy. The resistance is caused by a failure to trigger DDR signaling and apoptosis after chemotherapy induced DNA damage. These findings identify heterozygous SETD2 lossas a novel mechanism of chemotherapy resistance in leukemia and have implications for therapy selection and novel therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

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