Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer

Ji, Zhaodong; Shen, Yan; Xu, Feng; Kong, Yue; Shao, Yang; Meng, Jiao; Zhang, Xiaofei; Yang, Gong

doi:10.3389/fonc.2020.593017

Cited by 68 publications

(70 citation statements)

References 96 publications

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“…MAGL enzyme is overexpressed in a large variety of cells deriving from ovarian and colorectal cancers, and also has a key role in tumor progression [43,44]. Therefore, the new formulations of MAGL23 were tested on tumor cell lines inherent to ovarian [45] MAG23-AF and MAGL23 have comparable e cacy, in agreement with the results obtained from the nanocrystal characterization, which evidenced the maintenance of structural and chemical characteristics of the drug during the nanocrystallization procedure. Therefore, the drug delivery system allows to increase the water solubility without perturbing the molecule and consequently maintaining unaltered its activity on cells.…”

Section: Cell Viability Assaysupporting

confidence: 67%

Carrier Free Delivery System of Monoacylglycerol Lipase Hydrophobic Inhibitor for Cancer Therapy

Adeel¹,

Saorin²,

Boccalon³

et al. 2021

Preprint

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Background: Monoacylglycerol lipase (MAGL) is an emerging therapeutic target for cancer. It is involved in lipid metabolism and its inhibition impairs many hallmarks of cancer including cell proliferation, migration/invasion and tumor growth. For these reasons, our group has recently developed a potent reversible MAGL inhibitor (MAGL23), which showed promising anticancer activities. Here in, to improve its pharmacological properties, a nanoformulation based on nanocrystals coated with albumin was prepared for therapeutic applications. MAGL23 was solubilized by a nanocrystallization method with Pluronic F-127 and Cetyltrimethylammonium bromide (CTAB) as surfactants into an organic solvent and was recovered as nanocrystals in water after solvent evaporation. Finally, the solubilized nanocrystals were stabilized by human serum albumin to create a smart delivery carrier. Results: An in-silico prediction (lipophilicity, structure at different pH and solubility in water), as well as experimental study (solubility), have been performed to check the chemical properties of the inhibitor and nanocrystals. The solubility in water increases from less than 0.01 mg/mL (0.0008 mg/mL, predicted) up to 0.82 mg/mL in water. The formulated inhibitor maintained its potency in ovarian and colon cancer cell lines as the free drug. Furthermore, the system was thoroughly observed at each step of the solubilization process till the final formulation stage by different spectroscopic techniques and a comparative study was performed to check the effects of Pluronic F-127 and CTAB as surfactants. The formulated system is favorable to release the drug at physiological pH conditions (at pH 7.4, after 24h, less than 20% of compound is released). Conclusions: As per our knowledge, we are reporting the first ever nanoformulation of a MAGL inhibitor, which is promising as a therapeutic system where the MAGL enzyme is involved, especially for cancer therapeutic applications.

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Section: Cell Viability Assaysupporting

confidence: 67%

Carrier Free Delivery System of Monoacylglycerol Lipase Hydrophobic Inhibitor for Cancer Therapy

Adeel¹,

Saorin²,

Boccalon³

et al. 2021

Preprint

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“…We also propose to target components of the NF-κB signaling pathway or lipid metabolism in combination with PARPi. As discussed above, both processes were highly activated following PARP1i and are recognized as emerging targets for pharmacological interventions for the treatment of cancer (38). Moreover, a first clinical phase I study with the small molecule inhibitor TVB-2640 targeting fatty acid synthase FASN demonstrated antitumor activity in combination with chemotherapy in ovarian cancer patients (42).…”

Section: Nomination Of Candidate Parpi Combination Therapy Targetsmentioning

confidence: 99%

“…In conclusion, we nominate four drugs to inhibit aforementioned targets in combination with PARPi in future preclinical investigations. These drugs have already shown their anti-tumor potential as single agent or in combination treatment in a variety of pre-clinical and clinical studies (38,41,43,44).…”

Section: Nomination Of Candidate Parpi Combination Therapy Targetsmentioning

confidence: 99%

Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics

Franz

Coscia

Charaoui

et al. 2021

Preprint

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Poly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, which we confirmed in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and β-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-κB signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for combined therapeutic inhibition with PARP1. Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.

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“…Intra-abdominal tumors with a high frequency of omental metastases, such as ovarian cancer (OC), have become an important area of investigation revealing a role of adipocytes in promoting cancer lipid metabolism within the tumor microenvironment [2] . At the intracellular level, abnormal expression of key metabolic enzymes in fatty acid intake, synthesis, oxidation, and storage in OC cells has been associated with tumor-promoting properties [3] . Furthermore, for many of these enzymes, deregulation at the gene or/and protein level has been associated with prognostic implications in women with OC [3] .…”

mentioning

confidence: 99%

“…At the intracellular level, abnormal expression of key metabolic enzymes in fatty acid intake, synthesis, oxidation, and storage in OC cells has been associated with tumor-promoting properties [3] . Furthermore, for many of these enzymes, deregulation at the gene or/and protein level has been associated with prognostic implications in women with OC [3] . One such example is carnitine palmitoyltransferase (CPT), which catalyzes the decomposition of long-chain fatty acids and β-oxidation, and consists of two subtypes, CPT1 and CPT2 [3] .…”

mentioning

confidence: 99%

Loss of tumor suppressive properties of lipid metabolism enzyme CPT2 in ovarian carcinoma: Comment on “CPT2 down-regulation promotes tumor growth and metastasis through inducing ROS/NFκB pathway in ovarian cancer” by Zhang et al.

Vlachostergios

2021

Translational Oncology

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Lipid metabolism is an essential process in cancer growth and progression. It is highly relevant in tumors with an adipocyte-rich microenvironment, such as ovarian carcinoma (OC). Carnitine palmitoyltransferase 2 (CPT2) is a key enzyme in fatty acid oxidation (FAO) that functions as a tumor suppressor in OC. Downregulation of CPT2 is reportedly associated with poor prognosis of OC patients. At the cellular level, low CPT2 translates into reduced NADPH level and unopposed reactive-oxygen species (ROS)/nuclear factor kappa B (NFκB) signaling which are paralleled by induction of mesenchymal mediators, invasion and metastasis. While strategies to propagate the tumor suppressive properties of CPT2 have yet to be developed, a comprehensive approach of co-assessment and co-targeting of CPT2 and its family member CPT1, or/and other key FAO players with FAO-specific inhibitors or/and less specific inhibitors (e.g. targeting NFκB, STAT3) is worth pursuing to improve understanding of the metabolic aspects of OC and develop a lipid metabolism-centered therapeutic strategy that can benefit OC patients.

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Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer

Cited by 68 publications

References 96 publications

Carrier Free Delivery System of Monoacylglycerol Lipase Hydrophobic Inhibitor for Cancer Therapy

Carrier Free Delivery System of Monoacylglycerol Lipase Hydrophobic Inhibitor for Cancer Therapy

Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics

Loss of tumor suppressive properties of lipid metabolism enzyme CPT2 in ovarian carcinoma: Comment on “CPT2 down-regulation promotes tumor growth and metastasis through inducing ROS/NFκB pathway in ovarian cancer” by Zhang et al.

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