JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

Sun, Weili; Xie, Zuoquan; Liu, Yifu; Zhao, Dan; Wu, Zhixiang; Zhang, Dadong; Lv, Hao; Tang, Shuai; Jin, Nan; Jiang, Hualiang; Tan, Minjia; Ding, Jian; Luo, Cheng; Li, Jian; Huang, Min; Geng, Meiyu

doi:10.1158/0008-5472.can-15-1023

Cited by 65 publications

(73 citation statements)

References 49 publications

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“…Functionally, PDK1 enhances glucose consumption, attenuates lactate production, increases oxygen consumption, and reduces extracellular acidification [16, 51–53]. Consistently, our results showed that DIC elevates the glucose uptake and OCR, while decreasing the lactate production and ECAR in SKOV3 and A2780 cells (Fig 2).…”

Section: Discussionsupporting

confidence: 81%

“…Following the 24-h treatment, apoptosis was measured by staining the cells with annexin V and propidium iodide (PI) using the FITC Annexin V Apoptosis Detection Kit from BD Pharmingen (Shanghai, China). The cells were analyzed on a C6 Flow Cytometer, and the signal was quantified using C6 Software and a Workstation Computer (BD AccuriTM), as described previously [16]. …”

Section: Methodsmentioning

confidence: 99%

“…Positive cells containing a high level of ROS were detected by flow cytometry, as described previously [16]. …”

Section: Methodsmentioning

confidence: 99%

“…For example, dichloroacetate (DCA) targets the pyruvate-binding site [11, 12]; AZD7545 targets the lipoamide-binding pocket [13, 14]; and radicicol [15], JX06 [16], and VER-246608 [17] target the nucleotide-binding pocket of PDK1. However, no studies have investigated the anticancer effects of AZD7545 or VER-246608.…”

Section: Introductionmentioning

confidence: 99%

“…Although radicicol presents some antitumor activity [15], the underlying mechanisms remain unknown. DCA and JX06 have been demonstrated to target cancer development through modulating glucose metabolism, increasing reactive oxygen species (ROS), decreasing the mitochondrial membrane potential (MMP), and initiating apoptosis [16, 18]…”

Section: Introductionmentioning

confidence: 99%

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Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells

Zhang

et al. 2017

PLoS ONE

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

“…Positive cells containing a high level of ROS were detected by flow cytometry, as described previously [16]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells

Zhang

et al. 2017

PLoS ONE

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Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes

et al. 2022

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Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG) mimicking hyperglycemia in patientEC+/dia+. Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction‐sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06‐NPs) for drug delivery. It is found that in vitro JX06‐NPs have better inhibitory effect on the growth of IshikawaHG as well as patient‐derived EC cells (PDC) than JX06. Additionally, it is found that JX06‐NPs can accumulate to the tumor of EC‐bearing mouse with diabetes (miceEC+/dia+) after intravenous injection, and JX06‐NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+. Taken together, the study demonstrates that the combination of JX06‐NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+.

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Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation

Zhang

Cong

Zhang³

et al. 2018

Journal Cellular Physiology

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Patients with ovarian cancer frequently develop acquired drug resistance after the long-term chemotherapy, leading to disease progression. Enhanced epithelial-mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated. PDK1 was upregulated in cisplatin-resistant ovarian cancer cells. PDK1 knockdown in resistant cells led to increased sensitivity to cisplatin-induced cell death and apoptosis. PDK1 downregulation also reversed the EMT and cell motility in cisplatin-resistant cells. In a mouse xenograft model, tumors derived from PDK1-silenced ovarian cancer cells exhibited decreased tumor growth and EMT compared with control after the cisplatin treatment. Mechanistically, PDK1 overexpression led to increased phosphorylation of EGFR, and blocking EGFR kinase activity by erlotinib reversed cisplatin resistance induced by PDK1 overexpression. Furthermore, in patients with ovarian cancer, higher PDK1 and p-EGFR levels were associated with chemoresistance. These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR. Therefore, PDK1 may serve as a promising target to combat chemoresistance of ovarian cancer.

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JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

Cited by 65 publications

References 49 publications

Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells

Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes

Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation

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