Autophagy is upregulated in response
to metabolic stress, a hypoxic
tumor microenvironment, and therapeutic stress in various cancers
and mediates tumor progression and resistance to cancer therapy. Herein,
we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited
autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in
HCC cells, as indicated by the increased expression of LC3-II and
p62, inhibition of autophagosome–lysosome fusion, and suppression
of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve
its solubility and efficacy, we encapsulated C1 into
PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA)
nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented
distant metastasis while maintaining a desirable safety profile. Our
findings demonstrate that C1 combines autophagy modulation
and apoptosis induction in a single molecule, making it a promising
therapeutic option for HCC.