Bleomycins: towards better therapeutics

Chen, Jingyang; Stubbe, JoAnne

doi:10.1038/nrc1547

Cited by 573 publications

(534 citation statements)

References 94 publications

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“…This observation may suggest that the main toxic intermediates formed by bleomycin are those related to clustered DNA damage, including juxtaposed AP sites and/or 3 ¶ damagecontaining single-strand breaks, or complex DNA doublestrand breaks (48). Although APE1 has been shown to excise a synthetic mimic of a trapped 3 ¶-topoisomerase I protein (i.e., a 3 ¶-DNA tyrosyl residue; ref.…”

Section: Discussionmentioning

confidence: 93%

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

McNeill

Wilson

2007

Molecular Cancer Research

109

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Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals for the repair of abasic sites in DNA, as well as a variety of 3 ¶ damages that arise upon oxidation or as products of enzymatic processing. If left unrepaired, APE1 substrates can promote mutagenic and cytotoxic outcomes. We describe herein a dominant-negative form of APE1 that lacks detectable nuclease activity and binds substrate DNA with a 13-fold higher affinity than the wild-type protein. This mutant form of APE1, termed ED, possesses two amino acid substitutions at active site residues Glu 96 (changed to Gln) and Asp 210 (changed to Asn). In vitro biochemical assays reveal that ED impedes wild-type APE1 AP site incision function, presumably by binding AP-DNA and blocking normal lesion processing. Moreover, tetracycline-regulated (tet-on) expression of ED in Chinese hamster ovary cells enhances the cytotoxic effects of the laboratory DNA-damaging agents, methyl methanesulfonate (MMS; 5.4-fold) and hydrogen peroxide (1.5-fold). This MMS-induced, ED-dependent cell killing coincides with a hyperaccumulation of AP sites, implying that excessive DNA damage is the cause of cell death. Because an objective of the study was to identify a protein reagent that could be used in targeted gene therapy protocols, the effects of ED on cellular sensitivity to a number of chemotherapeutic compounds was tested. We show herein that ED expression sensitizes Chinese hamster ovary cells to the killing effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (also known as carmustine) and the chain terminating nucleoside analogue dideoxycytidine (also known as zalcitabine), but not to the radiomimetic bleomycin, the nucleoside analogue B-D-arabinofuranosylcytosine (also known as cytarabine), the topoisomerase inhibitors camptothecin and etoposide, or the cross-linking agents mitomycin C and cisplatin. Transient expression of ED in the human cancer cell line NCI-H1299 enhanced cellular sensitivity to MMS, 1,3-bis(2-chloroethyl)-1-nitrosourea, and dideoxycytidine, demonstrating the potential usefulness of this strategy in the treatment of human tumors.

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Section: Discussionmentioning

confidence: 93%

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

McNeill

Wilson

2007

Molecular Cancer Research

109

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“…23 When initiating pulmonary fibrosis with bleomycin, the most common administration route is intratracheal administration, which causes tissue necrosis, followed by an extensive inflammation and subsequent fibrosis. However, we have previously shown that repeated subcutaneous administration of a low-dose bleomycin results in a very different process, where fibrosis and inflammation develop in parallel resulting in increased proliferation rather than apoptosis.…”

Section: Discussionmentioning

confidence: 99%

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

Andersson-Sjöland

Karlsson

Rydell‐Törmänen

2016

Laboratory Investigation

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Pulmonary fibrosis is a grave diagnosis with insidious progression, generally considered as a consequence of aberrant epithelial wound healing and excessive scarring. This process is commonly modeled in animals by local bleomycin administration, resulting in peribronchial inflammation and subsequent fibrosis. We have previously described initiation and early development of distal pulmonary fibrosis following repeated subcutaneous bleomycin injections (systemic administration). The aim of this study was to identify mechanisms for the development of pulmonary fibrosis, which we hypothesize is related to endothelial stress and activation. Bleomycin was administered subcutaneously 3 times/ week during 0.33-4w, and parenchymal alterations were studied. In addition, we used microvascular endothelial cells to investigate effects of bleomycin in vitro. Our results confirmed that systemic administration of bleomycin exerts oxidative stress indicated by an increase in Sod1 at 0.33, 1, and 4w (Po0.05). Endothelial cells were activated (increased CD106 expression) from 1w and onwards (Po0.05), and p21 expression was increased 2-3 times throughout the study (Po0.05) as were the number of β-catenin-positive nuclei (Po0.001). Wnt3a was increased at 0.33, 1, and 4w (Po0.01) and Wnt5a from 1w and onwards (Po0.001). The present study suggests that bleomycin-induced reactive oxygen species (ROS) causes DNA stress affecting the endothelial niche, initiating repair processes including Wnt signaling. The repeated systemic administrations disrupt a normally fine-tuned balance in the Wnt signaling. In addition, pericyte differentiation was affected, which may have significant effects on fibrosis due to their ability to differentiate into myofibroblasts. We conclude that the endothelial niche may have an important role in the development of pulmonary fibrosis and warrants further investigations.

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“…Bleomycin induces oxidative DNA damage and subsequent cell death after formation of a complex with iron (or copper) and oxygen, which generates free radicals able to create DNA single‐ and double‐strand breaks (Hecht 2000; Chen and Stubbe 2005). Notably, this drug is also able to oxidatively damage other cellular targets such as RNA, proteins, and lipids (Chen and Stubbe 2005). Bleomycin‐induced adverse effects include GI disorders, myelosuppression, cutaneous reactions, and pulmonary toxicity, in particular severe and life‐threatening lung fibrosis (Froudarakis et al.…”

Section: Introductionmentioning

confidence: 99%

“…2015). The pathophysiology of bleomycin lung toxicity seems complex, but could involve oxidative stress, inflammation, and overproduction of profibrotic cytokine transforming growth factor‐ β (TGF β ) (Chen and Stubbe 2005; Kikuchi et al. 2011; Froudarakis et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Bleomycins: towards better therapeutics

Cited by 573 publications

References 94 publications

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

Role of endoplasmic reticulum stress in drug‐induced toxicity

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