To develop traditional medicines as modern
pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that
Artemisinin and its derivatives, which are clinically used
anti-malarial drugs, have significant effects against
ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that
dihydroartemisinin, one of the most active derivatives of
Artemisinin, directly targets
platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit
ovarian cancer cell growth and
metastasis.
Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its
ubiquitin-mediated degradation, which further inactivates downstream
phosphoinositide 3-Kinase and
mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and
metastasis of PDGFRα-positive
ovarian cancer in vitro and in vivo. A combinational treatment reveals that
dihydroartemisinin sensitizes
ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and
metastasis in human
ovarian cancer. Considering that
Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive
cancer patients. These findings also shed high light on future development of novel
Artemisinin-based targeted
therapy.