Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein
Citation: Cell Discovery
Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein
Xiaoguang Li 2
Qian Ba 2
Yanling Liu 1
Qingxi Yue 1
Peizhan Chen 1
Jingquan Li 2
Haibing Zhang 1
Hao Ying 1
Qiurong Ding 1
Haiyun Song 2
Hong Liu 0
Ruiwen Zhang 3
Hui Wang 1 2
0 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
1 Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China
2 School of Public health, Shanghai Jiao Tong University School of Medicine , Shanghai , China
3 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, TX , USA
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 plateletderived 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 PDGFRαpositive 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.
Introduction
Ovarian cancer poses a major health threat as the
sixth leading cause of cancer-related death in women in
developed countries and the eighth in developing
countries [
1
]. Clinically, it is the most lethal
gynecological malignancy, which is considered to be due to the
advanced stage of the disease at the time of diagnosis,
its highly metastatic nature, and the lack of effective
treatments for advanced disease [2]. Therefore, the
development of novel, effective and safe therapeutic
agents by ensuring a careful alignment of the target,
drug, patient and regimen design can lead to a better
outcome for ovarian cancer patients [3, 4].
Considerable efforts have been devoted to
evaluating several classes of conventional chemotherapeutic
agents for ovarian cancer therapy, such as paclitaxel
and platinum-based agents. However, clinical studies
indicate that the clinical response rates to these
treatments are low, and the clinical improvement is
marginal after therapy, especially in patients with advanced
disease (stages III–IV), which may be due to the late
diagnosis, persistent disease dormancy and drug
resistance [
3, 5, 6
]. It is hoped that basic and
translational research aimed at the development of targeted
therapy for ovarian cancer can identify etiological
factors for patients with heterogeneous ovarian
cancers, as well as predictive biomarkers for a better
histopathological and molecular diagnosis and for the
selection of an optimal therapeutic regimen, which will
provide a basis for individualized targeted therapy and
the discovery and development of more effective
therapeutic agents [
2, 5, 7
].
Artemisinin (ART) and its derivatives, which are
clinically used as anti-malarial agents worldwide, are
regarded as one of the greatest recent clinical successes
arising from traditional medicine [
8–11
]. Recently,
ART derivatives have been shown to have anticancer
properties, with low host toxicity [
11–13
]. One of
the main reasons for developing ART and its analogs
for cancer therapy is the safety profile of this class of
compounds. ART derivatives such as
dihydroartemisinin (DHA) and artesunate were found to be
active against a variety of tumor cell lines including
colon, breast, liver, lung, pancreatic cancer and
sensitized cancer cells to conventional chemotherapy
[
14–17
]. Additionally, human studies of individual
cases [
18, 19
] and clinical trials support ART
derivatives (...truncated)