PMID- 33640759
OWN - NLM
STAT- MEDLINE
DCOM- 20211101
LR  - 20211101
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 23
IP  - 3
DP  - 2021 Mar
TI  - High dose acetaminophen inhibits STAT3 and has free radical independent 
      anti-cancer stem cell activity.
PG  - 348-359
LID - S1476-5586(21)00007-5 [pii]
LID - 10.1016/j.neo.2021.02.001 [doi]
AB  - High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), 
      the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor 
      efficacy in early phase clinical trials. However, the mechanism of action (MOA) 
      of AAP's anticancer effects remains elusive. Using clinically relevant AAP 
      concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in 
      vivo in lung cancer and melanoma cells with diverse driver mutations. Associated 
      mechanisms were also studied. Our results demonstrated that AAP inhibited 3D 
      spheroid formation, self-renewal, and expression of CSC markers when human cancer 
      cells were grown in serum-free CSC media. Similarly, anti-CSC activity was 
      demonstrated in vivo in xenograft models - tumor formation following in vitro 
      treatment and ex-vivo spheroid formation following in vivo treatment. 
      Intriguingly, NAC, used to mitigate AAP's liver toxicity, did not rescue cells 
      from AAP's anti-CSC effects, and AAP failed to reduce glutathione levels in tumor 
      xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. 
      In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly 
      binds to STAT3 with an affinity in the low micromolar range and a high degree of 
      specificity for STAT3 relative to STAT1. These findings have high immediate 
      translational significance concerning advancing AAP with NAC rescue to 
      selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of 
      selective STAT3 inhibition has implications for developing rational anticancer 
      combinations and better patient selection (predictive biomarkers) for clinical 
      studies and developing novel selective STAT3 inhibitors using AAP's molecular 
      scaffold.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Pingali, Pavani
AU  - Pingali P
AD  - Section of Hematology and Oncology, Medicine Service, Hunter Holmes McGuire VA 
      Medical Center, Richmond, VA.
FAU - Wu, Y Jeffrey
AU  - Wu YJ
AD  - Department of Neurology, OHSU, Portland, OR.
FAU - Boothello, Rio
AU  - Boothello R
AD  - Section of Hematology and Oncology, Medicine Service, Hunter Holmes McGuire VA 
      Medical Center, Richmond, VA.
FAU - Sharon, Chetna
AU  - Sharon C
AD  - Section of Hematology and Oncology, Medicine Service, Hunter Holmes McGuire VA 
      Medical Center, Richmond, VA.
FAU - Li, Howard
AU  - Li H
AD  - Department of Pulmonology, Hunter Holmes McGuire VA Medical Center, Richmond, VA; 
      Department of Pulmonology, Virginia Commonwealth University Hospital, Richmond, 
      VA.
FAU - Sistla, Srinivas
AU  - Sistla S
AD  - Institute for Structural Biology, Drug Discovery and Development, Virginia 
      Commonwealth University, Richmond, VA.
FAU - Sankaranarayanan, Nehru Viji
AU  - Sankaranarayanan NV
AD  - Institute for Structural Biology, Drug Discovery and Development, Virginia 
      Commonwealth University, Richmond, VA.
FAU - Desai, Umesh R
AU  - Desai UR
AD  - Institute for Structural Biology, Drug Discovery and Development, Virginia 
      Commonwealth University, Richmond, VA; Department of Medicinal Chemistry, School 
      of Pharmacy, Virginia Commonwealth University, Richmond, VA.
FAU - Le, Anh T
AU  - Le AT
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado 
      Anschutz Medical Campus, Aurora, CO.
FAU - Doebele, Robert C
AU  - Doebele RC
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado 
      Anschutz Medical Campus, Aurora, CO.
FAU - Muldoon, Leslie L
AU  - Muldoon LL
AD  - Department of Neurology, OHSU, Portland, OR.
FAU - Patel, Bhaumik B
AU  - Patel BB
AD  - Section of Hematology and Oncology, Medicine Service, Hunter Holmes McGuire VA 
      Medical Center, Richmond, VA; Division of Hematology, Oncology, and Palliative 
      care, Department of Medicine, and Massey Cancer Center, Virginia Commonwealth 
      University. Richmond, VA. Electronic address: Bhaumik.patel@va.gov.
FAU - Neuwelt, Alexander
AU  - Neuwelt A
AD  - Section of Hematology and Oncology, Medicine Service, Hunter Holmes McGuire VA 
      Medical Center, Richmond, VA; Division of Hematology, Oncology, and Palliative 
      care, Department of Medicine, and Massey Cancer Center, Virginia Commonwealth 
      University. Richmond, VA. Electronic address: alexander.neuwelt@va.gov.
LA  - eng
GR  - P30 CA016059/CA/NCI NIH HHS/United States
GR  - P50 CA058187/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210226
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (AC133 Antigen)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Free Radicals)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 362O9ITL9D (Acetaminophen)
SB  - IM
MH  - AC133 Antigen/metabolism
MH  - Acetaminophen/administration & dosage/*pharmacology
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Biomarkers, Tumor
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Free Radicals/*metabolism
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Interleukin-6/antagonists & inhibitors
MH  - Lung Neoplasms
MH  - Neoplastic Stem Cells/*drug effects/*metabolism
MH  - STAT3 Transcription Factor/*antagonists & inhibitors/genetics/metabolism
PMC - PMC7920811
OTO - NOTNLM
OT  - Acetaminophen
OT  - Cancer stem cells
OT  - N-acetylcysteine
OT  - STAT3
EDAT- 2021/03/01 06:00
MHDA- 2021/11/03 06:00
PMCR- 2021/02/26
CRDT- 2021/02/28 20:36
PHST- 2020/11/24 00:00 [received]
PHST- 2021/02/03 00:00 [revised]
PHST- 2021/02/05 00:00 [accepted]
PHST- 2021/03/01 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/02/28 20:36 [entrez]
PHST- 2021/02/26 00:00 [pmc-release]
AID - S1476-5586(21)00007-5 [pii]
AID - 10.1016/j.neo.2021.02.001 [doi]
PST - ppublish
SO  - Neoplasia. 2021 Mar;23(3):348-359. doi: 10.1016/j.neo.2021.02.001. Epub 2021 Feb 
      26.