alpha-cyano-4-hydroxycinnamic-acid and Neoplasms

Poor selectivity, potential systemic toxicity and drug resistance are the main challenges associated with chemotherapeutic drugs. MCT1 and MCT4 and LAT1 play vital roles in tumour metabolism and growth by taking up nutrients and are thus potential targets for tumour therapy. An increasing number of studies have shown the feasibility of including these transporters as components of tumour-targeting therapy. Here, we summarize the recent progress in MCT1-, MCT4-and LAT1-based therapeutic strategies. First, protein structures, expression, relationships with cancer, and substrate characteristics are introduced. Then, different drug targeting and delivery strategies using these proteins have been reviewed, including designing protein inhibitors, prodrugs and nanoparticles. Finally, a dual targeted strategy is discussed because these proteins exert a synergistic effect on tumour proliferation. This article concentrates on tumour treatments targeting MCT1, MCT4 and LAT1 and delivery techniques for improving the antitumour effect. These innovative tactics represent current state-of-the-art developments in transporter-based antitumour drugs.

Topics: Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Large Neutral Amino Acid-Transporter 1; Molecular Structure; Monocarboxylic Acid Transporters; Muscle Proteins; Neoplasms; Symporters

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction