Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism

Naik, Ravi; Ban, Hyun Seung; Jang, Kyusic; Kim, Inhyub; Xu, Xuezhen; Harmalkar, Dipesh S.; Shin, Seong-Ah; Kim, Minkyoung; Kim, Bokyung; Park, Jae-Hyung; Ku, Bonsu; Oh, Soo‐Jin; Won, Misun; Lee, Kyeong

doi:10.1021/acs.jmedchem.7b01231

Cited by 28 publications

(29 citation statements)

References 32 publications

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“…This inhibitor blocks both cytoplasmic MDH1 and mitochondrial MDH2 enzymes. It has been shown that intraperitoneal administration of this inhibitor attenuates the development of colon cancer cell xenografts [ 113 ]. Further evaluations of MDH inhibitors, together with the development of specific GOT1, ME1 inhibitors are expected as therapeutic options in pancreatic cancer [ 114 ].…”

Section: Targeting Lipid Metabolism and Therapy Options For Cancermentioning

confidence: 99%

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Sunami

Rebelo

Kleeff

2017

Cancers

126

109

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Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.

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Section: Targeting Lipid Metabolism and Therapy Options For Cancermentioning

confidence: 99%

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Sunami

Rebelo

Kleeff

2017

Cancers

126

109

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“…Moreover, DEX downregulates the expression of liver fatty acid binding-associated genes and inhibits the expression of the liver mitochondrial matrix acyl-CoA dehydrogenases in mice, which are relevant to free fatty acid (FFA) import and fatty acid oxidation (FAO), respectively [15,16]. Glucose uptake and transport provide the main raw material for cells to synthesize amino acids, nucleotides, lipids, and adenosine triphosphate (ATP) which are necessary for survival and reproduction of cancer cells [17][18][19]. Malignant cells depend on rapid de novo fatty acid synthesis to support their development and growth [20].…”

Section: Introductionmentioning

confidence: 99%

“…(A) Schematic of the DEX treatment schedule. Mice were inoculated subcutaneously with 5 × 10 5 Lewis lung carcinoma (LLC) cells, and on days 7,9,11,13,15,17,19, and 21 post-inoculation, mice were intraperitoneally treated with 0.9% NaCl or various doses of DEX (2 mg/kg, 10 mg/kg, and 50 mg/kg). (B) Representative tumor growth in mice treated with 0.9% NaCl or various doses of DEX (n = 5-6 mice per group).…”

mentioning

confidence: 99%

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

Hua

et al. 2020

IJMS

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High-dose dexamethasone (DEX) is used to treat chemotherapy-induced nausea and vomiting or to control immunotherapy-related autoimmune diseases in clinical practice. However, the underlying mechanisms of high-dose DEX in tumor progression remain unaddressed. Therefore, we explored the effects of high-dose DEX on tumor progression and the potential mechanisms of its anti-tumor function using immunohistochemistry, histological examination, real-time quantitative PCR (qPCR), and Western blotting. Tumor volume, blood vessel invasion, and levels of the cell proliferation markers Ki67 and c-Myc and the anti-apoptotic marker Bcl2 decreased in response to high-dose DEX. However, the cell apoptosis marker cleaved caspase 3 increased significantly in mice treated with 50 mg/kg DEX compared with controls. Some genes associated with immune responses were significantly downregulated following treatment with 50 mg/kg DEX e.g., Cxcl9, Cxcl10, Cd3e, Gzmb, Ifng, Foxp3, S100a9, Arg1, and Mrc1. In contrast, the M1-like tumor-associated macrophages (TAMs) activation marker Nos2 was shown to be increased. Moreover, the expression of peroxisome proliferator-activated receptors α and γ (Pparα and Pparg, respectively) was shown to be significantly upregulated in livers or tumors treated with DEX. However, high-dose DEX treatment decreased the expression of glucose and lipid metabolic pathway-related genes such as glycolysis-associated genes (Glut1, Hk2, Pgk1, Idh3a), triglyceride (TG) synthesis genes (Gpam, Agpat2, Dgat1), exogenous free fatty acid (FFA) uptake-related genes (Fabp1, Slc27a4, and CD36), and fatty acid oxidation (FAO) genes (Acadm, Acaa1, Cpt1a, Pnpla2). In addition, increased serum glucose and decreased serum TG and non-esterified fatty acid (NEFA) were observed in DEX treated-xenografted tumor mice. These findings indicate that high-dose DEX-inhibited tumor progression is a complicated process, not only activated by M1-like TAMs, but also decreased by the uptake and consumption of glucose and lipids that block the raw material and energy supply of cancer cells. Activated M1-like TAMs and inefficient glucose and lipid metabolism delayed tumor cell growth and promoted apoptosis. These findings have important implications for the application of DEX combined with drugs that target key metabolism pathways for tumor therapy in clinical practice.

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“…Oxygen consumption was measured using an Oxytherm Clark-type electrode system (Hansatech, Norfolk, UK) as described previously with modifications 32 . HepG2 cells (2 × 10 7 ) were incubated with 2 µM LW1564 for 6 h and harvested, and then the OCR was measured for 5 min at 37°C with a thermos-regulated circulating system.…”

Section: Mitochondrial Respiration Assaymentioning

confidence: 99%

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation

Kim

Park

et al. 2020

Exp Mol Med

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Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.

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Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism

Cited by 28 publications

References 32 publications

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation

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