Evidence map›Paper›PMID 25720766›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2015

A small molecule with anticancer and antimetastatic activities induces rapid mitochondrial-associated necrosis in breast cancer.

Anja Bastian, Jessica E Thorpe, Bryan C Disch, Lora C Bailey-Downs, Aleem Gangjee, Ravi K V Devambatla, Jim Henthorn, Kenneth M Humphries, Shraddha S Vadvalkar, Michael A Ihnat

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
1.8field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 28 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Pharmacological modulation of mitochondrial ion channels.British journal of pharmacology · 2019
    Review
  7. Review
  8. TheGenes · 2018
    Review
  9. Article
  10. Article
  11. Article
  12. Review
  13. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 4 institutions in 1 country.

Anja BastianDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Jessica E ThorpeDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Bryan C DischDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Lora C Bailey-DownsDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Aleem GangjeeDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Ravi K V DevambatlaDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Jim HenthornDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Kenneth M HumphriesDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Shraddha S VadvalkarDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.).
Michael A IhnatDepartment of Pharmaceutical Sciences (A.B., J.E.T., B.C.D., M.A.I.), Department of Physiology (A.B.), Flow Cytometry and Imaging Laboratory (J.H.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; DormaTarg, Inc., Oklahoma City, Oklahoma (B.C.D., L.C.B.D., M.A.I.); Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (A.G., R.K.V.D.); and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (K.M.H., S.S.V.) michael-ihnat@ouhsc.edu.
University of Oklahoma Health Sciences Center · USOklahoma Medical Research Foundation · USDormaTarg (United States) · USDuquesne University · US

Funding

TUMOR RESISTANCE MECHANISMS TO ANTI-VEGF THERAPY IN PROSTATE CANCER (Sukyung Woo)P20GM103639 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI DHANASEKARAN, DANNY N. · 2012 to 2022
$21.3M
Project 5 VEGF Signaling in PhotoreceptorsP20GM104934 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI HAYS, FRANKLIN ALAN · 2012 to 2016
$10.8M
Single Agents with Designed Combination Chemotherapy PotentialR01CA136944 · NCI · DUQUESNE UNIVERSITY · PI GANGJEE, ALEEM · 2009 to 2010
$612k
NCI NIH HHS R01 CA136944NCI NIH HHS R01-CA136944NIGMS NIH HHS P20 GM103639NIGMS NIH HHS P20-GM103639NIGMS NIH HHS P20 GM104934
6 · The paper itself

Abstract

Therapy for treatment-resistant breast cancer provides limited options and the response rates are low. Therefore, the development of therapies with alternative chemotherapeutic strategies is necessary. AG311 (5-[(4-methylphenyl)thio]-9H-pyrimido[4,5-b]indole-2,4-diamine), a small molecule, is being investigated in preclinical and mechanistic studies for treatment of resistant breast cancer through necrosis, an alternative cell death mechanism. In vitro, AG311 induces rapid necrosis in numerous cancer cell lines as evidenced by loss of membrane integrity, ATP depletion, HMGB1 (high-mobility group protein B1) translocation, nuclear swelling, and stable membrane blebbing in breast cancer cells. Within minutes, exposure to AG311 also results in mitochondrial depolarization, superoxide production, and increased intracellular calcium levels. Additionally, upregulation of mitochondrial oxidative phosphorylation results in sensitization to AG311. This AG311-induced cell death can be partially prevented by treatment with the mitochondrial calcium uniporter inhibitor, Ru360 [(μ)[(HCO2)(NH3)4Ru]2OCl3], or an antioxidant, lipoic acid. Additionally, AG311 does not increase apoptotic markers such as cleavage of poly (ADP-ribose) polymerase (PARP) or caspase-3 and -7 activity. Importantly, in vivo studies in two orthotopic breast cancer mouse models (xenograft and allograft) demonstrate that AG311 retards tumor growth and reduces lung metastases better than clinically used agents and has no gross or histopathological toxicity. Together, these data suggest that AG311 is a first-in-class antitumor and antimetastatic agent inducing necrosis in breast cancer tumors, likely through the mitochondria.

Indexed as

AnimalsAntineoplastic AgentsApoptosisCalciumCell Line, TumorCell Membrane PermeabilityCell MovementCell ProliferationFemaleHomeostasisHumansIndolesMaleMembrane Potential, MitochondrialMiceMitochondria5-((4-methylphenyl)thio)-9H-pyrimido(4,5-b)indole-2,4-diamineAntineoplastic AgentsCalciumIndolesPyrimidinesSuperoxides

Identifiers

PMID25720766
PMCPMC4407723
OpenAlexW2012442151

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.