In Vivo Anticancer Activity of AZD3965: A Systematic Review.

Abstract

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords "AZD3965 in vivo" as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response.

• Authors: Ana Silva, Beatriz Antunes, Alberta Batista, Filipa Pinto-Ribeiro, Fátima Baltazar, Julieta Afonso
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 27 Issue 1 (Dec 29 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 35011413 (Publication Type: Journal Article, Meta-Analysis, Systematic Review)

Chemical References

• AZD3965
• Antineoplastic Agents
• Monocarboxylic Acid Transporters
• Pyrimidinones
• Symporters
• Thiophenes
• monocarboxylate transport protein 1
• Lactic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Disease Management
• Disease Progression
• Drug Evaluation, Preclinical
• Energy Metabolism (drug effects)
• Glycolysis
• Humans
• Lactic Acid (metabolism)
• Monocarboxylic Acid Transporters (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, etiology, metabolism, pathology)
• Pyrimidinones (pharmacology, therapeutic use)
• Signal Transduction
• Symporters (antagonists & inhibitors, metabolism)
• Thiophenes (pharmacology, therapeutic use)
• Tumor Microenvironment (drug effects)
• Warburg Effect, Oncologic (drug effects)
• Xenograft Model Antitumor Assays