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Targeting Intracellular Cholesterol is a Novel Therapeutic Strategy for Cancer Treatment.

ABSTRACT: Substantial data from cell culture and animal studies evidence the preventive effect of statins, cholesterol lowering-drugs, in regulation of cancer cell proliferation and metastasis. Various clinical studies also support this correlation between use of statin and the reduction of cancer incidence. However, in some cases, statins have failed to decrease the risk of cancer. Since, instead of serum cholesterol, intracellular cholesterol may play a crucial role in the regulation of tumorigenesis and metastasis. The mechanism by which cholesterol is stored within cancer cells may differ among cancer types and also in different individuals. This paper discusses the molecular detail to speculate the statin-sensitive cancer. It also highlights that statins may work better as anticancer therapy if it is used with the combination of a specific microRNA (miR).

SUBMITTER: Mandal CC

PROVIDER: S-EPMC4376010 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Targeting Intracellular Cholesterol is a Novel Therapeutic Strategy for Cancer Treatment.

Mandal Chandi C CC Rahman Md Mizanur MM

Journal of cancer science & therapy 20141201 12

Substantial data from cell culture and animal studies evidence the preventive effect of statins, cholesterol lowering-drugs, in regulation of cancer cell proliferation and metastasis. Various clinical studies also support this correlation between use of statin and the reduction of cancer incidence. However, in some cases, statins have failed to decrease the risk of cancer. Since, instead of serum cholesterol, intracellular cholesterol may play a crucial role in the regulation of tumorigenesis an ...[more]

PMID: 25821564

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Project description:BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.ConclusionONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Project description:BACKGROUND:Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS:Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS:EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS:These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

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Targeting Intracellular Cholesterol is a Novel Therapeutic Strategy for Cancer Treatment.

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Targeting Intracellular Cholesterol is a Novel Therapeutic Strategy for Cancer Treatment.

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