PMID- 37977042
OWN - NLM
STAT- MEDLINE
DCOM- 20240130
LR  - 20240130
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 68
DP  - 2023 Dec
TI  - A novel CPT1A covalent inhibitor modulates fatty acid oxidation and CPT1A-VDAC1 
      axis with therapeutic potential for colorectal cancer.
PG  - 102959
LID - S2213-2317(23)00360-9 [pii]
LID - 10.1016/j.redox.2023.102959 [doi]
LID - 102959
AB  - Colorectal cancer (CRC) is a common and deadly disease of the digestive system, 
      but its targeted therapy is hampered by the lack of reliable and specific 
      biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an 
      urgent and challenging task. Here we report that carnitine palmitoyltransferase 
      1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is 
      a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC 
      cells and that its inhibition by a secolignan-type compound, 
      2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia 
      dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate 
      that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the 
      mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial 
      permeability and reduced oxygen consumption and energy metabolism in CRC cells. 
      We also reveal that CPT1A expression correlates with the survival of 
      tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in 
      vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A 
      inhibitor and provides a rationale for its preclinical development as well as a 
      new strategy for CRC targeted therapy.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Hu, Anni
AU  - Hu A
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Wang, Hang
AU  - Wang H
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Xu, Qianqian
AU  - Xu Q
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Pan, Yuqi
AU  - Pan Y
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Jiang, Zeyu
AU  - Jiang Z
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Li, Sheng
AU  - Li S
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Qu, Yi
AU  - Qu Y
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China.
FAU - Hu, Yili
AU  - Hu Y
AD  - Experiment Center for Science and Technology, Nanjing University of Chinese 
      Medicine, Nanjing, 210046, China.
FAU - Wu, Hao
AU  - Wu H
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China.
FAU - Wang, Xinzhi
AU  - Wang X
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, 
      China; Jiangsu Key Laboratory of Research and Development in Marine Bio-resource 
      Pharmaceutics, Nanjing, 210046, China. Electronic address: 
      xinzhiwang@njucm.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20231110
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - 0 (Fatty Acids)
RN  - 0 (Voltage-Dependent Anion Channels)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - *Carnitine O-Palmitoyltransferase/antagonists & inhibitors/genetics/metabolism
MH  - *Colorectal Neoplasms/drug therapy/genetics
MH  - Fatty Acids/metabolism
MH  - Lipid Metabolism
MH  - Oxidation-Reduction
MH  - Voltage-Dependent Anion Channels/metabolism
PMC - PMC10692921
OTO - NOTNLM
OT  - 2,6-Dihydroxypeperomin B
OT  - CPT1A
OT  - Colorectal cancer
OT  - Covalent inhibitor
OT  - VDAC1
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships which have or could be 
      perceived to have influenced the work reported in this article.
EDAT- 2023/11/18 11:41
MHDA- 2023/12/06 06:42
PMCR- 2023/11/10
CRDT- 2023/11/17 18:17
PHST- 2023/09/24 00:00 [received]
PHST- 2023/11/02 00:00 [revised]
PHST- 2023/11/05 00:00 [accepted]
PHST- 2023/12/06 06:42 [medline]
PHST- 2023/11/18 11:41 [pubmed]
PHST- 2023/11/17 18:17 [entrez]
PHST- 2023/11/10 00:00 [pmc-release]
AID - S2213-2317(23)00360-9 [pii]
AID - 102959 [pii]
AID - 10.1016/j.redox.2023.102959 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Dec;68:102959. doi: 10.1016/j.redox.2023.102959. Epub 2023 Nov 
      10.