PMID- 35023320
OWN - NLM
STAT- MEDLINE
DCOM- 20220321
LR  - 20220321
IS  - 2198-3844 (Electronic)
IS  - 2198-3844 (Linking)
VI  - 9
IP  - 6
DP  - 2022 Feb
TI  - A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated 
      Breast Cancer.
PG  - e2102303
LID - 10.1002/advs.202102303 [doi]
LID - 2102303
AB  - Diabetes is directly related to the risk of breast cancer (BC) occurrence and 
      worsened BC prognosis. Currently, there are no specific treatments for 
      diabetes-associated BC. This paper aims to understand the fundamental mechanisms 
      of diabetes-induced BC progression and to develop personalized treatments. It 
      reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of 
      glucose import and glycolysis with metformin and NF-kappaB inhibitor (NF-kappaBi) while 
      blocking the export of excessive lactate via inhibiting monocarboxylate 
      transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It 
      demonstrates that the MRS shifts the metabolism of BC cells toward higher 
      production of lactate, blocks lactate secretion, prompts intracellular 
      acidification and induces significant cytotoxicity. Moreover, a novel MCT4 
      inhibitor CB-2 has been identified by structure-based virtual screening. A triple 
      combination of metformin, CB-2, and trabectedin, a drug that impedes NF-kappaB 
      signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS 
      elicits more potent cancer cell-killing effects under high glucose condition. 
      Animal model studies show that diabetic conditions promote the proliferation and 
      progression of BC xenografts in nude mice and that MRS treatment significantly 
      inhibits HG-induced BC progression. Therefore, inhibition of MCT4 combined with 
      metformin/NF-kappaBi is a promising cancer therapy, especially for 
      diabetes-associated BC.
CI  - (c) 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
FAU - Hao, Qiongyu
AU  - Hao Q
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
FAU - Huang, Zhimin
AU  - Huang Z
AD  - Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, 
      Department of Pathophysiology, Shanghai Jiao-Tong University School of Medicine, 
      Shanghai, 200025, China.
AD  - Department of Bioengineering, Rice University, Houston, TX, 77005, USA.
FAU - Li, Qun
AU  - Li Q
AD  - Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji 
      University, Shanghai, 200123, China.
FAU - Liu, Dingxie
AU  - Liu D
AD  - Bluewater Biotech LLC, New Providence, NJ, 07974, USA.
FAU - Wang, Piwen
AU  - Wang P
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
FAU - Wang, Kun
AU  - Wang K
AD  - Department of Breast Cancer, Cancer Center, Guangdong Provincial People's 
      Hospital & Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
FAU - Li, Jieqing
AU  - Li J
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
AD  - Department of Breast Cancer, Cancer Center, Guangdong Provincial People's 
      Hospital & Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
FAU - Cao, Wei
AU  - Cao W
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
FAU - Deng, Wenhong
AU  - Deng W
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
AD  - Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 
      430060, China.
FAU - Wu, Ke
AU  - Wu K
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
FAU - Su, Rui
AU  - Su R
AD  - College of Engineering, University of California, Berkeley, CA, 94720, USA.
FAU - Liu, Zhongmin
AU  - Liu Z
AD  - The Institute for Biomedical Engineering & Nano Science, Shanghai East Hospital, 
      Tongji University School of Medicine, Shanghai, 200120, China.
FAU - Vadgama, Jay
AU  - Vadgama J
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
FAU - Wu, Yong
AU  - Wu Y
AUID- ORCID: 0000-0002-1698-0897
AD  - Division of Cancer Research and Training, Department of Internal Medicine, 
      Charles Drew University of Medicine and Science, David Geffen UCLA School of 
      Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, 
      USA.
LA  - eng
GR  - NIH/NCI SC1CA200517/Accelerating Excellence in Translational Science Pilot/
GR  - Y-2020Sciclone/ms-0060/CSCO-Clinical Oncology Research Fund/
GR  - CTSI UL1TR000124/Department-of-Defense Breast Cancer Research Program/
GR  - BC043180/Department-of-Defense Breast Cancer Research Program/
GR  - SC1 CA200517/CA/NCI NIH HHS/United States
GR  - 1SC1GM121202/Accelerating Excellence in Translational Science Pilot/
GR  - NIH/NCI1U54CA14393/NIH-NIMHD/
GR  - U24 MD015970/MD/NIMHD NIH HHS/United States
GR  - 8217111643/National Natural Science Foundation of China/
GR  - G0814C01/Accelerating Excellence in Translational Science Pilot/
GR  - U56 CA101599-01/NIH-NIMHD/
GR  - SC1 GM135050-05/Accelerating Excellence in Translational Science Pilot/
GR  - SC1 GM135050/GM/NIGMS NIH HHS/United States
GR  - G0812D05/Accelerating Excellence in Translational Science Pilot/
GR  - 21PJ1412300/Shanghai Pujiang talent plan/
GR  - 19DZ2251000/Shanghai Engineering Research Center of Artificial Heart and Heart 
      Failure Medicine/
GR  - U54MD007598/NIH-NIMHD/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220112
PL  - Germany
TA  - Adv Sci (Weinh)
JT  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
JID - 101664569
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (Muscle Proteins)
RN  - 0 (SLC16A4 protein, human)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 9100L32L2N (Metformin)
RN  - ID0YZQ2TCP (Trabectedin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/metabolism/therapeutic use
MH  - Breast Neoplasms/complications/*drug therapy/*metabolism
MH  - Diabetes Mellitus, Experimental/complications/*metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Glucose/metabolism
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Hypoglycemic Agents/metabolism/therapeutic use
MH  - Lactic Acid/metabolism
MH  - Metformin/metabolism/*therapeutic use
MH  - Mice
MH  - Monocarboxylic Acid Transporters/*antagonists & inhibitors
MH  - Muscle Proteins/*antagonists & inhibitors
MH  - Prognosis
MH  - Trabectedin/metabolism/*therapeutic use
PMC - PMC8867195
OTO - NOTNLM
OT  - MCT4
OT  - breast cancer
OT  - diabetes
OT  - lactate
OT  - metabolic reprogramming
OT  - metformin
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/14 06:00
MHDA- 2022/03/22 06:00
PMCR- 2022/01/12
CRDT- 2022/01/13 06:38
PHST- 2021/10/08 00:00 [revised]
PHST- 2021/06/01 00:00 [received]
PHST- 2022/01/14 06:00 [pubmed]
PHST- 2022/03/22 06:00 [medline]
PHST- 2022/01/13 06:38 [entrez]
PHST- 2022/01/12 00:00 [pmc-release]
AID - ADVS3244 [pii]
AID - 10.1002/advs.202102303 [doi]
PST - ppublish
SO  - Adv Sci (Weinh). 2022 Feb;9(6):e2102303. doi: 10.1002/advs.202102303. Epub 2022 
      Jan 12.