Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG

Publication date: 30 October 2017 Source:International Journal of Pharmaceutics, Volume 532, Issue 1 Author(s): Bhushan S. Pattni, Aditi Jhaveri, Ivy Dutta, James D. Baleja, Alexei Degterev, Vladimir Torchilin Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80–90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analy...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research

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This article, however, is more of a commentary on high level strategy and the effects of regulation, coupled with a desire to forge ahead rather than hold back in the matter of treating aging, thus I concur with much more of what is said than is usually the case. For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm. At present, excellent reasoning suggests aging should be defined as a disease - indeed, aging has been referred to as "normal disease." Aging is the sum of all age-related diseases and this sum is the best biomarker of aging. Aging and its d...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of Navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we have developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant haematological cancer cell lines. In these models, resistance could be attributed neither to consistent changes in expression levels of the anti-apoptotic proteins nor interactions among different pro- and anti-apoptotic BCL-2 family members. Usin...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
ConclusionTaken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.
Source: Cancer and Metabolism - Category: Cancer & Oncology Source Type: research
Abstract Statins are commonly used in the middle-aged and elderly people for treatment of hyperlipidemia. Both alpha lipoic acid (ALA) and ellagic acid (EA) are natural antioxidants found in a normal diet. They can protect against cellular damage and induce cellular apoptosis in many types of cancer cells. Fluvastatin (FLV) was combined with ALA and EA in a nanostructured lipid carrier (NLC) formula. The prepared NLCs were imaged with a transmission electron microscope (TEM). Particle size and zeta potential and FLV entrapment efficiency (%EE) were measured, and the FLV release profile was constructed. Cellular vi...
Source: AAPS PharmSciTech - Category: Drugs & Pharmacology Authors: Tags: AAPS PharmSciTech Source Type: research
In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity. RNA Interference of ATP Synthase Subunits Slows Aging in Nematodes https://www.fightaging.org/archives/...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative ...
Source: Advanced Drug Delivery Reviews - Category: Drugs & Pharmacology Authors: Tags: Adv Drug Deliv Rev Source Type: research
Authors: Ishikawa T, Hosaka YZ, Beckwitt C, Wells A, Oltvai ZN, Warita K Abstract HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects in vitro and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Journal of Internal Medicine, EarlyView.
Source: Journal of Internal Medicine - Category: Internal Medicine Authors: Source Type: research
Authors: Jung Y, Lee SJ, Lee J, Noh WC, Nam SJ, Park BW, Bae YT, Kang SS, Park HK, Yoon JH, Kim JR, Cho SH, Kim LS, Moon BI, Jung SH, Lim CW, Kim SY, Park HY, Song J, Lee KM, Park SH, Jeong J, Park HL, Kim SW, Kwak BS, Kang SH, Cho YU, Gwak GH, Park YL, Kim SW, Han S Abstract Purpose: There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. Methods: Self-reported quality of life (QoL) scores were seria...
Source: Journal of Breast Cancer - Category: Cancer & Oncology Tags: J Breast Cancer Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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