SP1–CD44 Signalling Drives Gemcitabine Resistance via the Pentose Phosphate Pathway
- Pancreatic cancer cells resist gemcitabine when the pentose phosphate pathway raises dCTP pools that compete with the drug; this work places SP1–CD44 upstream, controlling G6PDH activity and NADPH.
- Inhibiting the axis re-sensitised cells to gemcitabine. Mithramycin A worked but is known to be toxic.
- A natural-product screen guided by docking and MD pointed to arenobufagin and bufalin as candidate SP1-binding sensitisers.
💡 Points Based on the abstract
SP1 is a transcription factor with a notoriously broad footprint, so any sensitiser needs a clean selectivity story, and bufadienolides are cardiac-glycoside-like compounds with a narrow safety margin, the very toxicity concern that sank mithramycin. The docking-based SP1 binding is a hypothesis; I'd want direct target engagement and an in vivo combination at tolerable exposure before calling these leads.
📄 Paper · Biochemical Pharmacology ↗ SP1–CD44 signaling modulates PPP-associated metabolism and gemcitabine sensitivity in pancreatic cancer cells