The synthetic oleanane triterpenoid CDDO-Me binds and inhibits pyruvate kinase M2

Soares, Iaci N.; Viana, Raiane; Trelford, Charles B.; Chan, Edward; Thai, Boun; Cino, Elio A.; Guglielmo, Gianni M. Di

doi:10.1007/s43440-019-00045-6

Cited by 8 publications

(7 citation statements)

References 48 publications

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“…The remaining compounds either showed a lower level of bioactivity compared to SM (pi-153) or were unable to affect motility of tumor cells at all (TM, pi-156). The obtained results are in line with published data: recently, we found that SM at identical concentration (0.5 µM) effectively inhibited migration of RAW264.7 macrophages [64]; furthermore, SM's structural analog CDDO-Me and its derivatives significantly reduced motility of both malignant [65][66][67][68][69] and non-malignant [70][71][72] cells at submicromolar concentrations (0.05-1 µM). Revealed differences in the level of inhibitory activity of investigated compounds against tumor cell motility are consistent with the level of their cytotoxicity.…”

Section: Discussionsupporting

confidence: 92%

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

et al. 2020

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Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. Further study showed that SM effectively blocked transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-β-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate.

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Section: Discussionsupporting

confidence: 92%

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

et al. 2020

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“…Additionally, we also found aerobic glycolysis was depressed in B28 treated cells due to reduction of glycolysis catalytic enzymes as PKM2, LDHA and ENO1. Similarly, recent study has demonstrated that oleanane triterpenoid CDDO-Me could bind and inhibit pyruvate kinase M2 [ 30 ]. Thus, we speculated that B28 acts as an oleanane triterpenoid derivative may retain this activity.…”

Section: Discussionmentioning

confidence: 99%

A synthesized olean-28,13β-lactam targets YTHDF1-GLS1 axis to induce ROS-dependent metabolic crisis and cell death in pancreatic adenocarcinoma

Huang

et al. 2022

Cancer Cell Int

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Background Pancreatic adenocarcinoma (PAAD) is a severe malignant with a 5-year survival rate of approximately 9%. Oleanolic acid is a well-known natural triterpenoid which exhibits pharmacological activities. We previously synthesized a series of oleanolic acid derivatives and evaluated the tumor-suppressive activity of olean-28,13β-lactam (B28) in prostate cancer. However, the detailed mechanism remains to be understood. Methods The anti-tumor activity of B28 in PAAD was confirmed by RTCA, colony formation assay and flow cytometry. GO and KEGG enrichment analyses were performed to analyze the differentially expressed genes (DEGs) obtained by RNA sequencing. The effects of B28 on cell bioenergetics were evaluated by seahorse analyzer. Lenti-virus packaged plasmids were performed to knockdown or overexpress target genes. Alteration of mitochondrial membrane potential, ROS and GSH/GSSG were measured by corresponding detection kits according to the manufacturer's protocol. Results We evaluated and confirmed the promising anti-tumor activity of B28 in vitro. RNA-seq profile indicated that multiple metabolic pathways were interrupted in B28 treated PAAD cells. Next, we demonstrated that B28 induces cellular bioenergetics crisis to inhibit PAAD cells growth and induce cell death. We further validated that cell cycle arrest, inhibition of cell growth, cell apoptosis and cell bioenergetics disruption were functionally rescued by ROS scavenger NAC. Mechanistically, we found glutamine metabolism was inhibited due to B28 administration. Moreover, we validated that down-regulation of GLS1 contributes to ROS generation and bioenergetics interruption induced by B28. Furthermore, we elucidated that YTHDF1-GLS1 axis is the potential downstream target of B28 to induce PAAD cell metabolic crisis and cell death. Finally, we also confirmed the anti-tumor activity of B28 in vivo. Conclusions Current study demonstrates B28 disrupts YTDFH1-GLS1 axis to induce ROS-dependent cell bioenergetics crisis and cell death which finally suppress PAAD cell growth, indicating that this synthesized olean-28,13β-lactam maybe a potent agent for PAAD intervention.

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“…CDDO‐Me binds directly and specifically to recombinant PKM2, leading to a reduction of its catalytic activity. Soares et al (2020) demonstrated that both CDDO‐Me and CDDO‐Im inhibited the migration of lung cancer (H1299) cells in scratch and transwell assays. It is preliminary results that need more investigation to control lung cancer metastasis.…”

Section: Synthetic Pkm2 Inhibitorsmentioning

confidence: 99%

Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics

El‐Far

Jaouni

et al. 2022

Phytotherapy Research

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Glycolysis is the primary source of energy for cancer growth and metastasis. The shift in metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis is called the Warburg effect. Cancer progression due to aerobic glycolysis is often associated with the activation of oncogenes or the loss of tumor suppressors. Therefore, inhibition of glycolysis is one of the effective strategies in cancer control. Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme overexpressed in breast, prostate, lung, colorectal, and liver cancers. Here, we discuss published studies regarding PKM2 inhibitors from natural products that are promising drug candidates for cancer therapy. We have highlighted the potential of natural PKM2 inhibitors for various cancer types. Moreover, we encourage researchers to evaluate the combinational effects between natural and synthetic PKM2 inhibitors. Also, further high‐quality studies are needed to firmly establish the clinical efficacy of natural products.

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The synthetic oleanane triterpenoid CDDO-Me binds and inhibits pyruvate kinase M2

Cited by 8 publications

References 48 publications

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

A synthesized olean-28,13β-lactam targets YTHDF1-GLS1 axis to induce ROS-dependent metabolic crisis and cell death in pancreatic adenocarcinoma

Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics

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