Optogenetic screening of MCT1 activity implicates a cluster of non-steroidal anti-inflammatory drugs (NSAIDs) as inhibitors of lactate transport

• Published in: PloS one 2024-12, Vol.19 (12), p.e0312492
• Main Authors: Wegner, Scott A, Kim, Hahn, Avalos, José L
• Format: Article
• Language: English
• Subjects: Affinity; Analysis; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anticancer properties; Biological Transport - drug effects; Biology and Life Sciences; Cancer therapies; Cell survival; Clusters; COX-2 inhibitors; Diclofenac; Drug delivery; Drug dosages; Drug Evaluation, Preclinical; Drug metabolism; Drug screening; Efflux; Estrogen; Estrogens; Humans; Indomethacin; Inflammation; Inhibitors; Isoforms; Lactic acid; Lactic Acid - metabolism; Light; Localization; Medicine and health sciences; Metabolism; Metabolites; Microenvironments; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Mutation; Natural products; Nonsteroidal anti-inflammatory drugs; Optogenetics; Physiological aspects; Piroxicam; Plasma; Proteins; Research and Analysis Methods; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Sulindac; Symporters - antagonists & inhibitors; Symporters - metabolism; Transcription factors; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0312492

Lactate transport plays a crucial role in the metabolism, microenvironment, and survival of cancer cells. However, current drugs targeting either MCT1 or MCT4, which traditionally mediate lactate import or efflux respectively, show limited efficacy beyond in vitro models. This limitation partly arises from the existence of both isoforms in certain tumors, however existing high-affinity MCT1/4 inhibitors are years away from human testing. Therefore, we conducted an optogenetic drug screen in Saccharomyces cerevisiae on a subset of the FDA-approved drug library to identify existing scaffolds that could be repurposed as monocarboxylate transporter (MCT) inhibitors. Our findings show that several existing drug classes inhibit MCT1 activity, including non-steroidal estrogens, non-steroidal anti-inflammatory drugs (NSAIDs), and natural products (in total representing approximately 1% of the total library, 78 out of 6400), with a moderate affinity (IC50 1.8-21 μM). Given the well-tolerated nature of NSAIDs, and their known anticancer properties associated with COX inhibition, we chose to further investigate their MCT1 inhibition profile. The majority of NSAIDs in our screen cluster into a single large structural grouping. Moreover, this group is predominantly comprised of FDA-approved NSAIDs, with seven exhibiting moderate MCT1 inhibition. Since these molecules form a distinct structural cluster with known NSAID MCT4 inhibitors, such as diclofenac, ketoprofen, and indomethacin, we hypothesize that these newly identified inhibitors may also inhibit both transporters. Consequently, NSAIDs as a class, and piroxicam specifically (IC50 4.4 μM), demonstrate MCT1 inhibition at theoretically relevant human dosages, suggesting immediate potential for standalone MCT inhibition or combined anticancer therapy.