riboflavin and Neoplasms

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

Cancer therapies usually suffer from poor targeting ability and serious side effects. Photoactivatable cancer therapy has the significant advantage of a high spatiotemporal resolution, but most photoactivatable prodrugs require decoration with stoichiometric photocleavable groups, which are only responsive to ultraviolet irradiation and suffer from low reaction efficiency. To tackle these challenges, we herein propose a photoactivation strategy with biogenic riboflavin as the photosensitizer to promote the in situ transformation of noncytotoxic dihydroalkaloid prodrugs dihydrochelerythrine (DHCHE), dihydrosanguinarine (DHSAN), and dihydronitidine (DHNIT) into anticancer alkaloid drugs chelerythrine (CHE), sanguinarine (SAN), and nitidine (NIT), respectively, which can efficiently kill cancer cells and inhibit in vivo tumor growth. Meanwhile, the photoactivatable transformation can be in situ monitored by green-to-red fluorescence conversion, which will contribute to easy controlling of the therapeutic dose. The proposed photoactivatable transformation mechanism was also explored by density functional theory (DFT) calculations. We believe this riboflavin-promoted and imaging-guided photoactivation strategy is promising for precise cancer therapy.

Topics: Neoplasms; Prodrugs