PMID- 37524206
OWN - NLM
STAT- MEDLINE
DCOM- 20230906
LR  - 20230918
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 215
DP  - 2023 Sep
TI  - Modulating MGMT expression through interfering with cell signaling pathways.
PG  - 115726
LID - S0006-2952(23)00317-9 [pii]
LID - 10.1016/j.bcp.2023.115726 [doi]
AB  - Guanine O(6)-alkylating agents are widely used as first-line chemotherapeutic 
      drugs due to their ability to induce cytotoxic DNA damage. However, a major 
      hurdle in their effectiveness is the emergence of chemoresistance, largely 
      attributed to the DNA repair pathway mediated by O(6)-methylguanine-DNA 
      methyltransferase (MGMT). MGMT plays an important role in removing the alkyl 
      groups from lethal O(6)-alkylguanine (O(6)-AlkylG) adducts formed by 
      chemotherapeutic alkylating agents. By doing so, MGMT enables tumor cells to 
      evade apoptosis and develop drug resistance toward DNA alkylating agents. 
      Although covalent inhibitors of MGMT, such as O(6)-benzylguanine (O(6)-BG) and 
      O(6)-(4-bromothenyl)guanine (O(6)-4-BTG or lomeguatrib), have been explored in 
      clinical settings, their utility is limited due to severe delayed hematological 
      toxicity observed in most patients when combined with alkylating agents. 
      Therefore, there is an urgent need to identify new targets and unravel the 
      underlying molecular mechanisms and to develop alternative therapeutic strategies 
      that can overcome MGMT-mediated tumor resistance. In this context, the regulation 
      of MGMT expression via interfering the specific cell signaling pathways (e.g., 
      Wnt/beta-catenin, NF-kappaB, Hedgehog, PI3K/AKT/mTOR, JAK/STAT) emerges as a promising 
      strategy for overcoming tumor resistance, and ultimately enhancing the efficacy 
      of DNA alkylating agents in chemotherapy.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Bai, Peiying
AU  - Bai P
AD  - Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of 
      Environment and Life, Beijing University of Technology, Beijing 100124, China.
FAU - Fan, Tengjiao
AU  - Fan T
AD  - Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of 
      Environment and Life, Beijing University of Technology, Beijing 100124, China; 
      Department of Medical Technology, Beijing Pharmaceutical University of Staff and 
      Workers, Beijing 100079, China.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Clinical Trials Center, National Cancer Center/National Clinical 
      Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences 
      and Peking Union Medical College, Beijing 100029, China.
FAU - Zhao, Lijiao
AU  - Zhao L
AD  - Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of 
      Environment and Life, Beijing University of Technology, Beijing 100124, China.
FAU - Zhong, Rugang
AU  - Zhong R
AD  - Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of 
      Environment and Life, Beijing University of Technology, Beijing 100124, China.
FAU - Sun, Guohui
AU  - Sun G
AD  - Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of 
      Environment and Life, Beijing University of Technology, Beijing 100124, China. 
      Electronic address: sunguohui@bjut.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20230729
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Alkylating Agents)
RN  - 9007-49-2 (DNA)
RN  - EC 2.1.1.63 (MGMT protein, human)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
SB  - IM
MH  - Humans
MH  - *O(6)-Methylguanine-DNA Methyltransferase/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Antineoplastic Agents, Alkylating/pharmacology
MH  - *Neoplasms/metabolism
MH  - Alkylating Agents/therapeutic use
MH  - Signal Transduction
MH  - DNA
MH  - DNA Modification Methylases/metabolism/therapeutic use
MH  - Tumor Suppressor Proteins/metabolism
MH  - DNA Repair Enzymes/metabolism/therapeutic use
OTO - NOTNLM
OT  - Alkylating agents
OT  - Cell signaling pathways
OT  - Cytotoxicity
OT  - Inhibitors
OT  - MGMT
OT  - Tumor resistance
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/08/01 01:08
MHDA- 2023/09/06 06:42
CRDT- 2023/07/31 19:12
PHST- 2023/06/11 00:00 [received]
PHST- 2023/07/28 00:00 [revised]
PHST- 2023/07/28 00:00 [accepted]
PHST- 2023/09/06 06:42 [medline]
PHST- 2023/08/01 01:08 [pubmed]
PHST- 2023/07/31 19:12 [entrez]
AID - S0006-2952(23)00317-9 [pii]
AID - 10.1016/j.bcp.2023.115726 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2023 Sep;215:115726. doi: 10.1016/j.bcp.2023.115726. Epub 2023 
      Jul 29.