Polyphyllin D: A Potent Anti-Cancer Saponin of the Chinese Herb "Paris polyphylla"

In 2001, a Chinese group led by Kwok-Pui Fung at Hong Kong University developed
an improved method for the chemical synthesis of a saponin called "Polyphyllin
D" (PPD), the major anti-cancer ingredient in a Chinese herb (root of Paris
polyphylla).

In 2005, his group reported that PPD solubilized in gamma CD (cyclodextrin)
suppresses almost completely the growth of breast cancer xonografts in mice
at the daily dose of 2-3 mg/kg. Interestingly, most of cancers sensitive to
this saponin appear to be among PAK1-dependent cancers such as breast,
prostate, liver, colon, stomach, pancreatic and lung cancers.

This year, two Chinese groups in China and US jointly revealed a molecular
mechanism underlying the anti-cancer action of this saponin (PPD). Just like
FK228, PPD inhibits the expression of VEGF and HIF-1 alpha. VEGF is essential
for tumor-induced angiogenesis. HIF-1 alpha (hif-1) is a hypoxia (oxygen
depletion)-inducible factor which is required for the expression of VEGF.
Furthermore, expression of hif-1 requires the oncogenic kinase PAK1 which
inactivates "FOXO" that is essential for the longevity. In other words, PPD
would contribute to the longevity, most likely by blocking PAK1.

The reason is as follows. Recently it was found that down-regulation of hif-1
prolongs the life span of a tiny nematode called C. elegans through "FOXO",
indicating that PPD, which down-regulates hif-1, would prolong the life-span at
least in two distinct ways through "FOXO". So we wonder if the transcription factor
hif-1 inactivates "FOXO" somehow, as does PAK1, and this natural product (PPD)
suppresses effectively the growth of both NF1 and NF2 tumors in vivo, as anti-PAK1
products such as Bio 30. Like Bio 30, PPD has no effect on the normal cell growth.

To be continued.

J Int Med Res. 2009 May-Jun;37(3):631-40.

Polyphyllin D Exerts Potent Anti-tumour Effects on Lewis Cancer Cells Under
Hypoxic Conditions.

Ma DD, Lu HX, Xu LS, Xiao W.

Department of Respiratory Medicine, Qilu Hospital, Shandong University,
Jinan, China; Department of Oral Biology, University of Missouri-Kansas
City, Kansas City, Kansas, USA.

Paris polyphylla has been used to treat cancer in China for many years and
components of the plant, such as polyphyllin D, may have potent antiproliferative
effects in vitro. To investigate the potential antitumour effects of polyphyllin
D on cancer cells under hypoxia, Lewis lung cancer cells and mouse tracheal
epithelial cells were cultured with or without polyphyllin D under normoxic
and hypoxic conditions. Proliferation and apoptosis of cells were assayed.
Real-time reverse transcription-polymerase chain reaction was used to quantify
the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and vascular
endothelial growth factor (VEGF) mRNA.

Polyphyllin D decreased cell proliferation, increased apoptosis and inhibited
expression of HIF-1alpha and VEGF mRNAs in Lewis cells. These effects were
greater under hypoxic than normoxic conditions. Polyphyllin D did not show
a cytotoxic effect in non-tumour cells (mouse skin fibroblasts and tracheal
epithelial cells). These results suggest that polyphyllin D potentially has
anticancer effects in vitro under hypoxia.


PLoS One. 2009 Jul 27;4(7):e6348.

The HIF-1 hypoxia-inducible factor modulates lifespan in C. elegans.

Zhang Y, Shao Z, Zhai Z, Shen C, Powell-Coffman JA.

Department of Genetics, Development, and Cell Biology, Iowa State University,
Ames, IA, USA.

During normal development or during disease, animal cells experience hypoxic
(low oxygen) conditions, and the hypoxia-inducible factor (HIF) transcription
factors implement most of the critical changes in gene expression that enable
animals to adapt to this stress. Here, we examine the roles of HIF-1 in
post-mitotic aging. We examined the effects of HIF-1 over-expression and
of hif-1 loss-of-function mutations on longevity in C. elegans, a powerful
genetic system in which adult somatic cells are post-mitotic.

We constructed transgenic lines that expressed varying levels of HIF-1 protein
and discovered a positive correlation between HIF-1 expression levels and
lifespan. The data further showed that HIF-1 acted in parallel to the SKN-1/NRF
and DAF-16/FOXO transcription factors to promote longevity. HIF-1 over-expression
also conferred increased resistance to heat and oxidative stress.

We isolated and characterized additional hif-1 mutations, and we found that
each of 3 loss-of-function mutations conferred increased longevity in normal
lab culture conditions, but, unlike HIF-1 over-expression, a hif-1 deletion
mutation did not extend the lifespan of daf-16 or skn-1 mutants.

We conclude that HIF-1 over-expression and hif-1 loss-of-function mutations
promote longevity by different pathways. These data establish HIF-1 as one of
the key stress-responsive transcription factors that modulate longevity in C.
elegans and advance our understanding of the regulatory networks that link
oxygen homeostasis and aging.