PMID- 34129882
OWN - NLM
STAT- MEDLINE
DCOM- 20211222
LR  - 20211222
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 907
DP  - 2021 Sep 15
TI  - Preclinical evidence of synergism between atovaquone and chemotherapy by 
      AMPK-dependent mitochondrial dysfunction.
PG  - 174256
LID - S0014-2999(21)00409-X [pii]
LID - 10.1016/j.ejphar.2021.174256 [doi]
AB  - Chemoresistance has been associated with increased reliance on mitochondrial 
      functions in many cancers, including lung cancer. Atovaquone is an anti-malaria 
      drug and mitochondrial inhibitor. In this work, we attempted to explore whether 
      atovaquone can be repurposed for lung cancer treatment to overcome 
      chemoresistance. We showed that atovaquone inhibited proliferation, colony 
      formation and survival in non-small cell lung cancer cell (NSCLC) cells. Of note, 
      the effective dose of atovaquone was clinically achievable. Combination index 
      value indicated that atovaquone and carboplatin were synergistic in inhibiting 
      NSCLC. The potent efficacy of atovaquone and its synergism with chemotherapeutic 
      drug were also demonstrated in NSCLC xenograft mice model. Mechanism studies 
      showed that the synergism between atovaquone and carboplatin was due to 
      atovaquone's ability in disrupting mitochondrial functions via specifically 
      inhibiting complex III induced oxygen consumption. Subsequently, atovaquone 
      activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of 
      rapamycin (mTOR) signaling. AMPK inhibition reversed the anti-NSCLC activity of 
      atovaquone, suggesting that the action of atovaquone is also dependent on AMPK. 
      Our work suggests that atovaquone is an attractive candidate for NSCLC treatment. 
      Our findings emphasize that inhibition of mitochondrial function is a promising 
      therapeutic strategy to enhance NSCLC chemosensitivity.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Xie, Fan
AU  - Xie F
AD  - Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze 
      University, Jingzhou, China.
FAU - Gong, Jianhua
AU  - Gong J
AD  - Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze 
      University, Jingzhou, China.
FAU - Tan, Hongxia
AU  - Tan H
AD  - Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze 
      University, Jingzhou, China.
FAU - Zhang, Han
AU  - Zhang H
AD  - Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze 
      University, Jingzhou, China.
FAU - Ma, Jingping
AU  - Ma J
AD  - Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze 
      University, Jingzhou, China. Electronic address: mjpjzhospital@hotmail.com.
LA  - eng
PT  - Journal Article
DEP - 20210612
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Line, Tumor
MH  - Mice
MH  - Mitochondria
MH  - *TOR Serine-Threonine Kinases
OTO - NOTNLM
OT  - AMPK/mTOR
OT  - Atovaquone
OT  - Mitochondrial function
OT  - NSCLC
OT  - Synergism
EDAT- 2021/06/16 06:00
MHDA- 2021/12/24 06:00
CRDT- 2021/06/15 20:12
PHST- 2020/11/28 00:00 [received]
PHST- 2021/05/31 00:00 [revised]
PHST- 2021/06/11 00:00 [accepted]
PHST- 2021/06/16 06:00 [pubmed]
PHST- 2021/12/24 06:00 [medline]
PHST- 2021/06/15 20:12 [entrez]
AID - S0014-2999(21)00409-X [pii]
AID - 10.1016/j.ejphar.2021.174256 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2021 Sep 15;907:174256. doi: 10.1016/j.ejphar.2021.174256. Epub 
      2021 Jun 12.