Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment

Yao-An Shen; Chi-Long Chen; Yi-Hsuan Huang; Emily Elizabeth Evans; Chun-Chia Cheng; Ya-Jie Chuang; Cissy Zhang; Anne Le

doi:10.1016/j.cbpa.2021.01.006

Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment

Curr Opin Chem Biol. 2021 Jun:62:64-81. doi: 10.1016/j.cbpa.2021.01.006. Epub 2021 Mar 12.

Authors

Yao-An Shen¹, Chi-Long Chen², Yi-Hsuan Huang³, Emily Elizabeth Evans³, Chun-Chia Cheng³, Ya-Jie Chuang³, Cissy Zhang⁴, Anne Le⁵

Affiliations

¹ Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
² Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
³ Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering Baltimore, MD 21218, USA. Electronic address: annele@jhmi.edu.

Abstract

Targeting glutamine catabolism has been attracting more research attention on the development of successful cancer therapy. Catalytic enzymes such as glutaminase (GLS) in glutaminolysis, a series of biochemical reactions by which glutamine is converted to glutamate and then alpha-ketoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle, can be targeted by small molecule inhibitors, some of which are undergoing early phase clinical trials and exhibiting promising safety profiles. However, resistance to glutaminolysis targeting treatments has been observed, necessitating the development of treatments to combat this resistance. One option is to use synergy drug combinations, which improve tumor chemotherapy's effectiveness and diminish drug resistance and side effects. This review will focus on studies involving the glutaminolysis pathway and diverse combination therapies with therapeutic implications.

Keywords: Combination therapy; Glutaminase; Glutaminolysis; Metabolic reprogramming; Therapeutic resistance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Combined Chemotherapy Protocols / chemistry*
Antineoplastic Combined Chemotherapy Protocols / metabolism
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Citric Acid Cycle / drug effects*
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Glutaminase / antagonists & inhibitors
Glutaminase / metabolism*
Glutamine / metabolism*
Glycogen / chemistry
Glycogen / metabolism
Humans
Ketoglutaric Acids / metabolism
Lactic Acid / chemistry
Lactic Acid / metabolism
Signal Transduction

Substances

Antineoplastic Agents
Enzyme Inhibitors
Ketoglutaric Acids
Glutamine
Lactic Acid
Glycogen
Glutaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding