Background: Hepatocellular Carcinoma (HCC), the second leading cause of cancer-related mortality
with over half a million new cases diagnosed annually in the world, accounts for nearly 70% of cancer deaths in
parts of Asia and Africa. Podophyllum, one of the important members of the lignane class of natural products
derived from plants in Podophyllum peltatum L., has been shown to suppress tumor growth in various cancers.
However, the effects of Podophyllum compounds on HCC and the mechanisms for its tumor-suppressive function
Methods: A molecular docking study was employed to the analysis of the interaction between compounds and
their targeted proteins. Cell proliferation was measured by MTT assay. Western blot analysis was used to evaluate
protein expression. qRT-PCR was performed to assess RNA expression.
Results: Molecular docking analysis was consistent with the beneficial effect of fluorine atom substituent in the
3-position of 2-aminopyridine in our previous study. Also, P-3F and D-3F displayed the most potent cytotoxicities
against PLC/PRF/5 with p53-R249S and weakest inhibition of L02 (normal liver cell) growth. However,
these derivatives had no effect on the suppression of HepG2 (wild-type p53) and Hep3B (p53-null) proliferation
significantly. Further study showed that both compounds increase γ-H2AX expression in PLC/PRF/5 cell, along
with repression of the c-Myc activation, purportedly by induction of p53 level and transcriptional activation.
Conclusion: The results suggested that podophyllum derivatives containing fluorine atom in the 3-position of 2-
aminopyridine could inhibit the growth of HCC harboring p53-R249S by restoring the activity of p53 with decreasing
the level of c-Myc.