Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells.
Wenjia Zhang,Jing Su,Huadan Xu,Shanshan Yu,Yanan Liu,Yong Zhang,Liankun Sun,Ying Yue,Xiaoli Zhou +8 more
TLDR
DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro.Abstract:
Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.read more
Citations
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Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice.
TL;DR: The primary objective of this review is to describe what the authors know to date of the active compounds in the natural products, along with their pharmacologic action and molecular or specific targets.
Journal ArticleDOI
Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance.
Milad Ashrafizadeh,Ali Zarrabi,Kiavash Hushmandi,Kiavash Hushmandi,Mahshad Kalantari,Reza Mohammadinejad,Tahereh Javaheri,Gautam Sethi +7 more
TL;DR: The various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure are highlighted.
Journal ArticleDOI
Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism
TL;DR: Recently, tumor metabolism has gained interest as a reason of chemoresistance in tumors and chemotherapeutic drugs in combination with metabolism targeting approaches has been found promising in overcoming therapeutic resistance.
Journal ArticleDOI
Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy.
TL;DR: In this paper, a review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors and emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations.
Journal ArticleDOI
PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling.
Michelle K.Y. Siu,Yu-Xin Jiang,Jing-Jing Wang,Thomas Ho-Yin Leung,Siew Fei Ngu,Annie N.Y. Cheung,Hextan Y.S. Ngan,Karen K. L. Chan +7 more
TL;DR: This is the first report to demonstrate an association between PDK1 and survival in patients with ovarian cancer, supporting its efficacy as a valuable prognostic marker and therapeutic molecular target for the disease.
References
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The Warburg Effect: How Does it Benefit Cancer Cells?
TL;DR: Several proposed explanations for the function of Warburg Effect are analyzed, emphasize their rationale, and discuss their controversies.
Journal ArticleDOI
A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth
Sébastien Bonnet,Stephen L. Archer,Joan Allalunis-Turner,Alois Haromy,Christian Beaulieu,Richard B. Thompson,Christopher T. Lee,Gary D. Lopaschuk,Lakshmi Puttagunta,Sandra Bonnet,Gwyneth Harry,Kyoko Hashimoto,Christopher J. Porter,Miguel A. Andrade,Bernard Thébaud,Evangelos D. Michelakis +15 more
TL;DR: The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted and the orally available DCA is a promising selective anticancer agent.
Journal ArticleDOI
Metabolic Modulation of Glioblastoma with Dichloroacetate
Evangelos D. Michelakis,Gopinath Sutendra,Peter Dromparis,Linda Webster,Alois Haromy,E. Niven,C. Maguire,John R. Mackey,Dorcas Fulton,Bassam Abdulkarim,Michael Sean McMurtry,K. C. Petruk +11 more
TL;DR: Dichloroacetate appears to be safe to give to humans at doses that are required for pyruvate dehydrogenase inhibition, and can be added to a growing group of metabolic modulators that may prove useful in cancer therapy.
Journal ArticleDOI
Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.
TL;DR: The previously unsuspected collaboration between HIF-1 and dysregulated c-Myc is reported and additional insights into the regulation of VEGF and the Warburg effect are provided, which describes the propensity for cancer cells to convert glucose to lactate.
Journal ArticleDOI
PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer
Fanny Dupuy,Sébastien Tabariès,Sylvia Andrzejewski,Zhifeng Dong,Julianna Blagih,Matthew G. Annis,Atilla Omeroglu,Dongxia Gao,Samuel Leung,Eitan Amir,Mark Clemons,Adriana Aguilar-Mahecha,Mark Basik,Emma E. Vincent,Julie St-Pierre,Russell G. Jones,Peter M. Siegel +16 more
TL;DR: It is demonstrated that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients, and the data implicatePDK1 as a key regulator of metabolism and metastatic potential in breast cancer.
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