Labdane-type diterpenoids from Hypoestes phyllostachya inhibit pancreatic cancer stem cells

Ten previously undescribed labdane diterpenoids, hypochins A-J (1-10), were isolated from the aerial parts of Hypoestes phyllostachya with white spots. Their structures and absolute configurations were elucidated through comprehensive spectroscopic characterization, including IR, HRMS, NMR, electronic circular dichroism analysis, single-crystal X-ray diffraction, and biosynthetic considerations. Notably, compound 10 represents a rare labdane diterpenoid incorporating 16,15;19,6-dilactone units. Compound 1 exhibited potent inhibition of sphere formation in pancreatic cancer stem cells (PCSCs), which are known to drive tumor growth and contribute to resistance against cancer therapies. The suppression of PCSCs by 1 was confirmed by the down-regulation of cancer stem cell markers CD44, CD133, Oct-4, Sox-2, ALDH1A1, Musashi1, CXCR4, and PON1. Further investigations demonstrated that 1 suppressed the self-renewal of PANC-1 cells and inhibited their migration and invasion by suppressing epithelial-mesenchymal transition. Moreover, the selectivity of 1 against PCSCs and pancreatic cancer cells was evaluated through apoptosis analysis. Compared to paclitaxel, which is effective against cancer cells but inactive on PCSCs, compound 1 induced marked apoptosis in PCSCs, demonstrating its selectivity as a PCSC-targeted inhibitor. These results address the critical need for therapies that specifically target PCSCs, which play a crucial role in pancreatic cancer progression.