Doxorubicin, DNA torsion, and chromatin dynamics

Yang, Fan; Teves, Sheila S; Kemp, Christopher J.; Henikoff, Steven

doi:10.1016/j.bbcan.2013.12.002

Cited by 484 publications

(503 citation statements)

References 76 publications

Supporting

Mentioning

455

Contrasting

Unclassified

Order By: Relevance

“…A statistical functional analysis of these nonsynonymous variants using Web-based Gene Set Analysis Toolkit (WebGestalt) (13) showed that three representative terms were enriched in the Gene Ontology (GO) molecular function category, namely "carbohydrate derivative binding," "nucleoside binding," and "ATP-dependent helicase activity" (SI Appendix, Table S2). These findings further support the findings of previous studies that DOX inhibits the enzyme topoisomerase II by intercalating between two base pairs of the DNA double helix (14).…”

Section: Resultssupporting

confidence: 92%

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Han

Jun

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In vitro prediction of the probable rapid emergence of resistance to a drug in tumors could act to winnow out potential candidates for further costly development. We have developed a microfluidic device consisting of ∼500 hexagonal microcompartments that provides a complex ecology with wide ranges of drug and nutrient gradients and local populations. This ecology of a fragmented metapopulation induced the drug resistance in stage IV U87 glioblastoma cells to doxorubicin in 7 d. Exome and transcriptome sequencing of the resistant cells identified mutations and differentially expressed genes. Gene ontology and pathway analyses of the genes identified showed that they were functionally relevant to the established mechanisms of doxorubicin action. Specifically, we identified (i) a frame-shift insertion in the filamin-A gene, which regulates the influx and efflux of topoisomerase II poisons; (ii) the overexpression of aldo-keto reductase enzymes, which convert doxorubicin into doxorubicinol; and (iii) activation of NF-κB via alterations in the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway from mutations in three genes (CARD6, NSD1, and NLRP13) and the overexpression of inflammatory cytokines. Functional experiments support the in silico analyses and, together, demonstrate the effects of these genetic changes. Our findings suggest that, given the rapid evolution of resistance and the focused response, this technology could act as a rapid screening modality for genetic aberrations leading to resistance to chemotherapy as well as counter selection of drugs unlikely to be successful ultimately.

show abstract

Section: Resultssupporting

confidence: 92%

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Han

Jun

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…4 Doxorubicin has different modes of action such as topoisomerase II poisoning, DNA adduct formation, oxidative stress, histones eviction, and ceramide overproduction. 5 Contrary to its high activity against SCLC, it is relatively ineffective against NSCLC. Even in SCLC, doxorubicin-based chemotherapy regimens frequently fail due to inherent and acquired resistance.…”

Section: Introductionmentioning

confidence: 99%

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

El‐Awady

Hersi

Al-Tunaiji

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

Abbreviations: 5AZA, 5-aza-2 0 -deoxycytidine; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; DNMT, DNA methyltransferase; HAT, histone acetyl transferase; HDAC, histone deacetylase; NSCLC, non-small cell lung cancer; PBS, phosphate-buffered saline; SCLC, small-cell lung cancer; TSA, trichostatin A; 5mc, 5-methyl cytosine.Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/ novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 -4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.

show abstract

“…Doxorubcin (DOX), also known as adriamycin, is widely used as an anti-tumor drug. Its mechanisms of action include the induction of apoptosis of tumor cells by intercalating into their DNA to inhibit its transcription and initiate a DNA damage response (5). DOX-based chemotherapy is used against a wide range of cancer types, including ovarian (6), breast (7) and bladder cancer (8) as well as HCC (9).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-101 sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis via targeting Mcl-1

Tian

Chen

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. MicroRNAs (miRNAs/miRs) are important regulators of multiple cellular processes, and their dysregulation is a common event in tumorigenesis, including the development of hepatocellular carcinoma (HCC). Studies have shown that certain miRNAs are associated with resistance to chemotherapy or drug sensitization; however, the underlying mechanisms have largely remained elusive. Multiple drug resistance is a major barrier for the treatment of advanced HCC. In the present study, miR-101 was observed to be downregulated in a panel of HCC cell lines, suggesting that it has a tumor suppressor role.

show abstract

Doxorubicin, DNA torsion, and chromatin dynamics

Cited by 484 publications

References 76 publications

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

MicroRNA-101 sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis via targeting Mcl-1

Contact Info

Product

Resources

About