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.
Highlights
Cancer remains one of the biggest public health issues around the world
One of the many emerging therapeutic approaches is based on the metabolic particularities presented by cancer cells, mainly characterized by a switch from oxidative phosphorylation (OXPHOS) to accelerated glycolysis regardless of oxygen availability, resulting in intensive production of lactate [1]
Cancer cells upregulate a series of pH regulators, including monocarboxylate transporters (MCTs) that extrude lactate to the tumor microenvironment (TME) via a proton-linked mechanism [2,3]
Summary
Cancer remains one of the biggest public health issues around the world. One of the many emerging therapeutic approaches is based on the metabolic particularities presented by cancer cells, mainly characterized by a switch from oxidative phosphorylation (OXPHOS) to accelerated glycolysis regardless of oxygen availability, resulting in intensive production of lactate [1]. Cancer cells upregulate a series of pH regulators, including monocarboxylate transporters (MCTs) that extrude lactate to the tumor microenvironment (TME) via a proton-linked mechanism [2,3]. The overall profile of MCT overexpression in most tumors, focusing on MCT1, and its relation to aggressiveness and poor survival rates has launched several investigations aiming to identify viable inhibitors [4,5]. One of those inhibitors, AZD3965, has proven to be an effective and specific MCT1 inhibitor, which has already entered clinical trials in the UK [6]. We aimed to analyze the in vivo studies performed using AZD3965 in different types of cancer and infer the evidence of its pre-clinical effectiveness
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