PMID- 32883024
OWN - NLM
STAT- MEDLINE
DCOM- 20210414
LR  - 20210414
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 9
DP  - 2020 Sep 1
TI  - Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by 
      Blocking Autophagy Recycling.
LID - 10.3390/cells9092013 [doi]
LID - 2013
AB  - The greatest challenge in cancer therapy is posed by drug-resistant recurrence 
      following treatment. Anticancer chemotherapy is largely focused on targeting the 
      rapid proliferation and biosynthesis of cancer cells. This strategy has the 
      potential to trigger autophagy, enabling cancer cell survival through the 
      recycling of molecules and energy essential for biosynthesis, leading to drug 
      resistance. Autophagy recycling contributes amino acids and ATP to restore mTOR 
      complex 1 (mTORC1) activity, which leads to cell survival. However, autophagy 
      with mTORC1 activation can be stalled by reducing the ATP level. We have 
      previously shown that cytosolic NADH production supported by aldehyde 
      dehydrogenase (ALDH) is critical for supplying ATP through oxidative 
      phosphorylation (OxPhos) in cancer cell mitochondria. Inhibitors of the 
      mitochondrial complex I of the OxPhos electron transfer chain and ALDH 
      significantly reduce the ATP level selectively in cancer cells, terminating 
      autophagy triggered by anticancer drug treatment. With the aim of overcoming drug 
      resistance, we investigated combining the inhibition of mitochondrial complex I, 
      using phenformin, and ALDH, using gossypol, with anticancer drug treatment. Here, 
      we show that OxPhos targeting combined with anticancer drugs acts synergistically 
      to enhance the anticancer effect in mouse xenograft models of various cancers, 
      which suggests a potential therapeutic approach for drug-resistant cancer.
FAU - Lee, Jae-Seon
AU  - Lee JS
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
AD  - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei 
      University, Seoul 03722, Korea.
FAU - Lee, Ho
AU  - Lee H
AD  - Department of System Cancer Science, Graduate School of Cancer Science and 
      Policy, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea.
FAU - Jang, Hyonchol
AU  - Jang H
AUID- ORCID: 0000-0003-1436-457X
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
FAU - Woo, Sang Myung
AU  - Woo SM
AUID- ORCID: 0000-0003-3786-4403
AD  - Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
FAU - Park, Jong Bae
AU  - Park JB
AD  - Department of System Cancer Science, Graduate School of Cancer Science and 
      Policy, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea.
FAU - Lee, Seon-Hyeong
AU  - Lee SH
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
FAU - Kang, Joon Hee
AU  - Kang JH
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
FAU - Kim, Hee Yeon
AU  - Kim HY
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
FAU - Song, Jaewhan
AU  - Song J
AD  - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei 
      University, Seoul 03722, Korea.
FAU - Kim, Soo-Youl
AU  - Kim SY
AD  - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, 
      Gyeonggi-do 10408, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200901
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Antineoplastic Agents)
RN  - DD5K7529CE (Phenformin)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - KAV15B369O (Gossypol)
SB  - IM
MH  - Aldehyde Dehydrogenase/antagonists & inhibitors
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Autophagy/*drug effects
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Drug Synergism
MH  - Electron Transport Complex I/antagonists & inhibitors
MH  - Gossypol/pharmacology/*therapeutic use
MH  - HT29 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Mitochondria/drug effects/metabolism
MH  - Neoplasms/*drug therapy/*metabolism/pathology
MH  - Oxidative Phosphorylation/*drug effects
MH  - Phenformin/pharmacology/*therapeutic use
MH  - Xenograft Model Antitumor Assays
PMC - PMC7565066
OTO - NOTNLM
OT  - ATP production
OT  - aldehyde dehydrogenase
OT  - cancer metabolism
OT  - energy metabolism
OT  - oxidative phosphorylation (OxPhos)
COIS- The authors declare no conflict of interest.
EDAT- 2020/09/05 06:00
MHDA- 2021/04/15 06:00
PMCR- 2020/09/01
CRDT- 2020/09/05 06:00
PHST- 2020/08/10 00:00 [received]
PHST- 2020/08/28 00:00 [revised]
PHST- 2020/08/29 00:00 [accepted]
PHST- 2020/09/05 06:00 [entrez]
PHST- 2020/09/05 06:00 [pubmed]
PHST- 2021/04/15 06:00 [medline]
PHST- 2020/09/01 00:00 [pmc-release]
AID - cells9092013 [pii]
AID - cells-09-02013 [pii]
AID - 10.3390/cells9092013 [doi]
PST - epublish
SO  - Cells. 2020 Sep 1;9(9):2013. doi: 10.3390/cells9092013.