PMID- 25720766
OWN - NLM
STAT- MEDLINE
DCOM- 20150526
LR  - 20181113
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 353
IP  - 2
DP  - 2015 May
TI  - A small molecule with anticancer and antimetastatic activities induces rapid 
      mitochondrial-associated necrosis in breast cancer.
PG  - 392-404
LID - 10.1124/jpet.114.220335 [doi]
AB  - 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 [(mu)[(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.
CI  - Copyright (c) 2015 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Bastian, Anja
AU  - Bastian A
AD  - Department 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.).
FAU - Thorpe, Jessica E
AU  - Thorpe JE
AD  - Department 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.).
FAU - Disch, Bryan C
AU  - Disch BC
AD  - Department 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.).
FAU - Bailey-Downs, Lora C
AU  - Bailey-Downs LC
AD  - Department 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.).
FAU - Gangjee, Aleem
AU  - Gangjee A
AD  - Department 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.).
FAU - Devambatla, Ravi K V
AU  - Devambatla RK
AD  - Department 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.).
FAU - Henthorn, Jim
AU  - Henthorn J
AD  - Department 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.).
FAU - Humphries, Kenneth M
AU  - Humphries KM
AD  - Department 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.).
FAU - Vadvalkar, Shraddha S
AU  - Vadvalkar SS
AD  - Department 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.).
FAU - Ihnat, Michael A
AU  - Ihnat MA
AD  - Department 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.
LA  - eng
GR  - P20 GM103639/GM/NIGMS NIH HHS/United States
GR  - R01-CA136944/CA/NCI NIH HHS/United States
GR  - R01 CA136944/CA/NCI NIH HHS/United States
GR  - P20 GM104934/GM/NIGMS NIH HHS/United States
GR  - P20-GM103639/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150226
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (5-((4-methylphenyl)thio)-9H-pyrimido(4,5-b)indole-2,4-diamine)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - 0 (Pyrimidines)
RN  - 11062-77-4 (Superoxides)
RN  - SY7Q814VUP (Calcium)
SB  - IM
EIN - J Pharmacol Exp Ther. 2017 Jan;360(1):225. PMID: 27994003
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/toxicity
MH  - Apoptosis/drug effects
MH  - Calcium/metabolism
MH  - Cell Line, Tumor
MH  - Cell Membrane Permeability/drug effects
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Homeostasis/drug effects
MH  - Humans
MH  - Indoles/*pharmacology/toxicity
MH  - Male
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mitochondria/*drug effects/metabolism
MH  - Necrosis/*chemically induced
MH  - Neoplasm Metastasis
MH  - Pyrimidines/*pharmacology/toxicity
MH  - Rats
MH  - Superoxides/metabolism
MH  - Time Factors
MH  - Triple Negative Breast Neoplasms/*pathology
MH  - Xenograft Model Antitumor Assays
PMC - PMC4407723
EDAT- 2015/02/28 06:00
MHDA- 2015/05/27 06:00
PMCR- 2016/05/01
CRDT- 2015/02/28 06:00
PHST- 2015/02/28 06:00 [entrez]
PHST- 2015/02/28 06:00 [pubmed]
PHST- 2015/05/27 06:00 [medline]
PHST- 2016/05/01 00:00 [pmc-release]
AID - jpet.114.220335 [pii]
AID - JPET_220335 [pii]
AID - 10.1124/jpet.114.220335 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2015 May;353(2):392-404. doi: 10.1124/jpet.114.220335. Epub 
      2015 Feb 26.