Cancer of the corpus uteri and cervix uteri, collectively ranks second among new
cancer cases in women after
breast cancer. Therefore, investigation of new
anticancer agents and identifying new molecular targets presents a challenge to improve effectiveness of
chemotherapy. In this study, antiproliferative activity of
flavonoids derived from the buds of
silver birch and downy birch was evaluated in
endometrial cancer Ishikawa cells and
cervical cancer HeLa cells. It was found that flavanol
santin reduced viability of both cell lines better than other
flavonoids, including
apigenin and
luteolin. Moreover, this activity was slightly higher than that induced by the
chemotherapy drug,
cisplatin.
Santin promoted intrinsic and extrinsic apoptosis pathways in
cancer cells, but it had low toxicity in normal fibroblasts. The mechanisms of impairing
cancer cell viability included induction of oxidative
proline catabolism, however in different ways in the cell lines used. In HeLa cells, increase of
proline oxidation was due to activation of p53 leading to
proline oxidase upregulation. In contrast, in Ishikawa cells, having basal
proline oxidase level significantly higher than HeLa cells,
santin treatment decreased its expression. Nevertheless,
proline oxidation was induced in these cells since
santin increased expression and activity of
prolidase, an
enzyme providing
proline from protein degradation. In both cell lines,
proline oxidation was associated with generation of
reactive oxygen species leading to reduction in cell viability. Our findings reveal the involvement of
proline oxidase in induction of apoptosis by
santin and identify a role of
prolidase in
proline oxidase-dependent apoptosis.