hydroxycitrate cancer

United States Am. As chronic CR is contraindicated for many cancer patients at risk for weight loss, cachexia, and immunosuppression, intermittent CR, fasting-mimicking diets, low carbohydrate/ketogenic diets, or CR mimetic drugs may be more suitable. PubMed Provided by the Springer Nature SharedIt content-sharing initiative. Seyfried, T. N. & Shelton, L. M. Cancer as a metabolic disease. Torres M, Parets S, Fernndez-Daz J, Beteta-Gbel R, Rodrguez-Lorca R, Romn R, Llad V, Rossell CA, Fernndez-Garca P, Escrib PV. From Krebs to clinic: glutamine metabolism to cancer therapy. The patients had been heavily pre-treated. Due to the dual role of autophagy in cancer, autophagy inducers and inhibitors have become targets for cancer therapy [27]. Clinical studies are ongoing and will inform on the potential use of these dietary and drug treatments alongside conventional treatments. Nat Rev Cancer. Cancer cells utilize acetyl CoA as a synthetic precursor to fuel proliferation and growth ; thus, blocking acetyl CoA synthesis is a rational approach to specifically target cancer metabolism. Reports 7, 9850, https://doi.org/10.1038/s41598-017-10464-1 (2017). 2012;12(3):18195. Similarly, CR also maintains immunological fitness of CD4+ T cells during aging to enhance cancer immunotherapy, specifically OX40-agonist immunotherapy [50]. Robitaille, J., Chen, J. and transmitted securely. A treatment course using gemcitabine plus -lipoic acid and hydroxycitrate gave highly promising results. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S, Mirisola M, Quinn DI, Dorff TB, et al. One patient was unable to receive i.v. Google Scholar. 2010;7:74. Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, Pollak MN, Hursting SD. In vivo antitumor activity of the lipoic acid and calcium hydroxycitrate combination on the LL/2 cancer model. 2015;34(7):85680. & Frieden, B. R. Information dynamics in carcinogenesis and tumor growth. Recent research in our lab showed that combining autophagy inhibition with a CR regimen reduced tumor growth more than either treatment alone [20]. Chronic CR is challenging to employ in cancer patients, and therefore intermittent fasting, CR mimetic drugs, or alternative diets (such as a ketogenic diet), may be more suitable. Currie E, Schulze A, Zechner R, Walther TC, Farese Jr RV. 2011;13(9):101623. Schwartz, L. et al. For further details see34. 1). Concentrations of adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) have been measured in normal and cancer cells, extracted from fresh human colon tissues. CR, fasting, and FMD also reduce pro-inflammatory cytokines in the circulation and in the tumor microenvironment niche, as well as reduced leptin, insulin, IGF-1, and glucose. These results pave the way for new strategies in metabolic therapy and in silico metabolic drug design. The Malabar tamarind is the only practical source of this supplement. Hyperosmolarity causes inflammation through the methylation of protein phosphatase 2a. Although several in vitro and in vivo studies have indicated that resveratrol can enhance anticancer treatments [64], Fukui et al. Bonnet, S. et al. Liver Physiol. In a KRAS-driven lung cancer model, Guo et al. However, the limited success of these chemotherapeutic agents opened avenues for new strategies. Investig. Article Belltall A, Mazzinari G, Diaz-Cambronero O, Eroles P, Argente Navarro MP. Harvie M, Howell A. All patients had failed standard chemotherapy and were offered only palliative care by their referring oncologist. 2b). Cancer Ther. Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats. These diets mimic many of the metabolic and anti-inflammatory properties of CR, including reduced blood glucose, insulin, and IGF-1 [69], as well as the oxidation of fatty acids and generation of ketones. Mukherjee P, Mulrooney TJ, Marsh J, Blair D, Chiles TC, Seyfried TN. 2015;3:3. While in the short-term studies will need to focus on the safety and added benefit to current therapies, future studies may also focus on the potential of CR in enhancing the response to lower doses of chemotherapy and radiation therapy. Do not use this product if you are breastfeeding. Nat Biotechnol. 2004 Nov;14(4):567-73. doi: 10.1016/j.thorsurg.2004.06.006. Sci Transl Med. Another CR mimetic, metformin, is a biguanide commonly used to treat type 2 diabetes by inhibiting gluconeogenesis through indirect activation of AMPK, thus reducing blood glucose and insulin to levels observed in CR mice [58]. Addition of exogenous IGF-1 leads to the partial reversal of the anticancer effects of CR, further supporting the role of IGF-1 in tumorigenesis [10]. Therefore, more preclinical studies should be performed prior to progressing to clinical trials examining resveratrol as an adjuvant anticancer therapy. Randomized trials are necessary to confirm these preliminary data. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. Cite this article. In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. Experiments were stopped at day 59 since PBS group reaches a lethal tumor volume. Therapeutic targets in cancer cell metabolism and autophagy. Clin Cancer Res. While preclinical studies are mounting on the effects of intermittent CR in combination with chemotherapy and radiation therapy, clinical studies are slow to follow, likely due to the concerns listed above. Caloric restriction maintains OX40 agonist-mediated tumor immunity and CD4 T cell priming during aging. Oncol. This site needs JavaScript to work properly. Since Metformin is used as an hypoglycemic drug in type II diabeties, it slows down insulin secretion and cell proliferation by decoupling mitochondrial respiration throughout the ETC. 2010;9(22):44746. For the model integrating metabolic therapy, the therapeutic molecules are supplied within the blood inlet flux (F) feeding the capillaries blood volume (i.e. Interestingly, retrospective epidemiological studies have shown that diabetic patients with long-term Metformin treatment have a reduced risk of developing cancer26,29. Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Furthermore, as CR is anti-inflammatory, chronic CR may be a concern to patients with immunodeficiency or following surgery. implemented the calculations. A pre-clinical investigation thus consisted to further evaluate the effect of METABLOC combined to new drugs (Metformin and Diclofenac) on the growth of transplanted LL/2 Lewis lung carcinoma into mice. This combination of calcium citrate (HCA) and lipoic acid (ALA) does reduce tumor growth, as reported in our previous works (Fig. Eng. In this work, we present a metabolic therapy specifically targeting the activity of specific enzymes of central carbon metabolism, combining the METABLOC bi-therapeutic drugs combination (Alpha. The predicted tumor volume is within the standard deviations of experimental tumor volume. Authors Ahmed Ismail 1 , Ahmed S Doghish 2 , Bakheet E M Elsadek 3 , Salama A Salama 4 , Amr D Mariee 5 Affiliations tumor cells microenvironment). Cancers (Basel). 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Bioprocess Biosyst. Ward PS, Thompson CB. Mulrooney TJ, Marsh J, Urits I, Seyfried TN, Mukherjee P. Influence of caloric restriction on constitutive expression of NF-kappaB in an experimental mouse astrocytoma. Consumption of glucose by the tumor cells is linear, until reaching limitation level at the end of the 25th day and totally consumed 59 days after incubation. 2016;30(1):14760. Oppermann, H., Levinson, A. D., Varmus, H. E., Levintow, L. & Bishop, J. M. Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src). Despite it not being clear whether administration of CR would support tumor growth in these circumstances, it is thought that transformed cells lack the metabolic adaptability to respond to altered substrate availability, having already invested heavily in metabolic reprograming and thus being more sensitive to increased pressure on ketone metabolism and fatty acid oxidation than normal cells [24]. 2011;71(9):3196201. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. This treatment, in combination with conventional chemotherapy, has. Patients and methods: Karnofsky status was between 50 and 80. New Drugs 30, 200211, https://doi.org/10.1007/s10637-010-9552-x (2012). PLoS One. 1 It is also a potent antioxidant that is used as a health supplement. These very primary results suggest the lack of toxicity and the probable efficacy of metabolic treatment in chemoresistant advanced carcinoma. A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Fasting has also been shown to control circadian clock genes, the expression of which usually oscillates at specific intervals throughout the day and is coupled to processes such as oxidative stress response and DNA damage repair [44]. Live Chat. Short-term fasting has been shown to improve chemotherapeutic treatment with etoposide [40], mitoxantrone, oxaliplatin [41], cisplatin, cyclophosphamide, and doxorubicin [42] in transgenic and transplant mouse models of neuroblastoma, fibrosarcoma, glioma, melanoma, and breast and ovarian cancers. Klamt, S. & Gilles, E. Minimal cut sets in biochemical reaction networks. While the antitumorigenic effects of CR are well established, the mechanism behind this relationship remains unclear, though it is believed that the tumor suppressive effects are mediated, in part, by enhanced apoptosis within tumors, modulation of systemic signals such as insulin-like growth factor (IGF)-1, insulin, metabolic and inflammatory pathways, as well as by reduced angiogenesis. 3 and the system of differential equations in methods) has been set up from previous models describing the simulation of Chinese Hamster Ovary cells (CHO) growth on different media for the production of monoclonal antibodies34. 1c). Hanahan and Weinberg described common molecular machinery involved in regulating cell proliferation, differentiation and death. Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner. SBM is supported by a T32 training fellowship from the National Institutes of Health (8T32LM012420-02). When less may be more: calorie restriction and response to cancer therapy. Biomass synthesis is described as the incorporation of amino acids, intermediate metabolites and palmitic acid. Combining lipoic acid to methylene blue reduces the Warburg effect in CHO cells: From TCA cycle activation to enhancing monoclonal antibody production. To obtain NAD+/NADH ratio decreases upon glucose exhaustion. Soc. In the meantime, to ensure continued support, we are displaying the site without styles Primary sites were lung carcinoma (n=2), colonic carcinoma (n=2), ovarian carcinoma (n=1), esophageal carcinoma (n=1), uterine sarcoma (n=1), cholangiocarcinoma (n=1), parotid carcinoma (n=1) and unknown primary (n=1). Within the scope of cancer research, a meta-analysis of preclinical rodent models evaluated the impact of CR across multiple cancer types and through a variety of tumor models [6]; overall, CR displayed a 75.5% reduction in tumor incidence. Opin. Gastrointest. New Users of Metformin Are at Low Risk of Incident Cancer A cohort study among people with type 2 diabetes. Intermittent energy restriction induces changes in breast gene expression and systemic metabolism. 2009;460(7253):3925. 2021 May 26;11(6):344. doi: 10.3390/metabo11060344. By using this website, you agree to our 261, 221228, https://doi.org/10.1016/j.jbiotec.2017.05.001 Bioinformatics Solutions for Big Data Analysis in Life Sciences presented by the German Network for Bioinformatics Infrastructure (2017). In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Sabine Peres. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). BMC Cancer. Many tumors undergo metabolic reprogramming, including enhanced fatty acid oxidation and glutaminolysis in addition to increased glucose metabolism [21,22,23]. In cancer cells, PDH has been shown to be inhibited whereas ACL is overexpressed. Treatment with a combination of -lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. PubMedGoogle Scholar. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancers Achilles heel. Energy restriction and the prevention of breast cancer. and JavaScript. The https:// ensures that you are connecting to the The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. Carter LG, D'Orazio JA, Pearson KJ. Saudi. Hatzivassiliou, G. et al. Nutrition. Several phase II trials are currently underway to evaluate metformin as a potential combination therapy, including one non-small cell lung cancer study that involves a low carbohydrate diet arm. Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, et al. official website and that any information you provide is encrypted Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction? In summary, CR and its mimetics show promise as supportive anticancer therapies. Isral, M. & Schwartz, L. The metabolic advantage of tumor cells. 2015;54(2):11023. Google Scholar. Karnofsky status was between 50 and 80. This has opened new markets for the pharmaceutical industry while defining new approaches in cancer therapy. We also set up a kinetic metabolic model of tumor growth in order to characterize the effect of metabolic therapies on tumor metabolism. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Clipboard, Search History, and several other advanced features are temporarily unavailable. Nat Cell Biol. CR can also aid in immunosurveillance of tumors by reducing Treg populations that inhibit cytotoxic CD8+ T cells. 2015;2(1):1325. 2011;30(30):330516. Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids. The AMPK/mTOR axis also controls autophagy, a process through which proteins, macronutrients and organelles are enveloped in double-membraned vesicles and degraded into building blocks that can then be shuttled into synthetic pathways. 357, 112122, https://doi.org/10.1016/j.jtbi.2014.04.035 (2014). 2005;19(4):66774. Cancer Cell. Bowers LW, Rossi EL, O'Flanagan CH, de Graffenried LA, Hursting SD. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcinoma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). Cancer Cell 8, 311321, https://doi.org/10.1016/j.ccr.2005.09.008 (2005). The thin curves represent tumor volumes for each single mouse. They were treated with a combination of lipoic acid at 600 mg i.v. {V}_{blood}\\ \frac{d{V}_{tumor}}{dt} & = & \frac{dX}{dt}+\frac{dVblood}{dt}\end{array}$$, $$\min (\sum _{n=1}^{N}\,\sum _{t=1}^{T}\,{(\frac{{Y}_{n,t}^{\exp }-{Y}_{n,t}(p)}{{\sigma }_{n,t}})}^{2})$$, https://doi.org/10.1038/s41598-019-39109-1. The dynamical system is written as follow and is explained in supplementary materials: Parameters value where first taken from previous works on CHO cells34,36, when not available for cancer or human cells in the literature or databanks. Resveratrol and cancer: focus on in vivo evidence. CAS Drops of ethanol were added to completely dissolve lipoic acid in PBS solution. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? 2013;1(1):10. Hyperosmolarity Triggers the Warburg Effect in Chinese Hamster Ovary Cells and Reveals a Reduced Mitochondria Horsepower. Biol. Initiation of the PI3K/AKT pathway promotes decreased apoptosis by disrupting the BCL2-Bad complex, increases protein synthesis via mTOR activation, and increases glucose metabolism by inhibiting GSK-3 [13]. We especially thank Jean-Marc Steyaert and Marcel Levy Nogueira for interesting discussions and suggestions for the experimental part of this article. Dose-dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin-like growth factor-1. Cancer Discov. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. CR, fasting, or fasting-mimicking diets (FMDs) cause reduced Akt/mTOR and Ras signaling in normal cells, resulting in senescence, reduced growth, and protection from cytotoxic treatment, while in tumor cells, oncogenic signals remain and cells are sensitive to anti-mitotic therapies. 2012;1(2):27588. Cancer Cell 13, 472482, https://doi.org/10.1016/j.ccr.2008.05.005 (2008). In this work, we demonstrate . Keywords: sharing sensitive information, make sure youre on a federal Model simulations show a growth plateau at around 873mm3 as for the experimental data (87370mm3). Nevertheless, although IGF-1 signaling is a promising anticancer target, drugs targeting the pathway have been largely unsuccessful [12]. 2014;33(1):21729. & Bost, F. Metformine et cancer: pass, prsent, avenir. The network integrates pathways of the central carbon metabolism (CCM) such as glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, lipogenesis, the oxidative phosphorylation and pathways of amino acid metabolism. Furthermore, increasing preclinical and human evidence suggests that CR reduces inflammation [11, 28, 29]. Epub 2022 Jun 1. Schwartz L, Guais A, Isral M, Junod B, Steyaert JM, Crespi E, Baronzio G, Abolhassani M. Invest New Drugs. Our model predicts metabolic therapies-induced reversed Warburg effect on tumor cells. doi:10.1126/scitranslmed.aai8700. 2b). (a) Lactic acid is first eliminated by the blood flow and then accumulates with tumor growth. PMC In our metabolic network, there are 1058 minimal cut sets which prevent the tumor growth (X). 2014;34(2):97380. Article Publishers note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The tumor is continuously fed from the network of capillaries, with a global blood flow rate (F) of composition C0 at tumor inlet. BMJ 330, 13041305, https://doi.org/10.1136/bmj.38415.708634.F7 (2005). Selman C, Kerrison ND, Cooray A, Piper MD, Lingard SJ, Barton RH, Schuster EF, Blanc E, Gems D, Nicholson JK, et al. Cookies policy. CAS 1e,g). FOIA Int J Obes. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. You are using a browser version with limited support for CSS. 2011;35(5):71427. MeSH Epub 2010 Oct 8. Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, et al. Appl Physiol Nutr Metab. The site is secure. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, et al. Gatenby, R. A. Careers. Role of alpha-lipoic acid in counteracting paclitaxel- and doxorubicin-induced toxicities: a randomized controlled trial in breast cancer patients. 2009;69(19):750711. Diclofenac is also an old drug currently used as an anti-inflammatory agent. Similarly, a study from Bonnet and colleagues (2006) demonstrated the efficacy of a small molecule, Dichloroacetate, in restoring PDH activity in cancer cells23. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. It is native to southern India, where it is dried and used extensively in curries. Thus, versatile therapeutic strategies based on H 2 O 2 as a reaction substrate to generate hydroxyl radical (OH) have been used as a prospective therapeutic method to boost anticancer efficiency. CAS . J.D.M., M.J., L.S. The core metabolism of cancer cells integrates glycolysis, the pentose phosphate pathway, the citric acid cycle, lipogenesis and amino acids metabolism. Google Scholar. Google Scholar. Reports 23, 14071416 (2010). Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. OTC Weight-Loss Aid Hydroxycitrate Promotes Autophagy, May Help Cure Cancer P. D. Mangan March 26, 2015 14 Comments Hydroxycitrate is an over-the-counter supplement made from the plant Garcinia cambogia, and it has been promoted for weight loss. AMPK induces expression of metabolic control genes, including SIRT1, resulting in increased fatty acid oxidation and glutaminolysis to provide auxiliary substrates when glucose is scarce [18]. CAS A summary of past and current clinical trials of intermittent CR, fasting-mimicking diets, and ketogenic diets in combination with anticancer therapies is included in Table 1. 2008;8:122. 2011;71(13):448493. Lee C, Raffaghello L, Longo VD. Patients and methods: Sci. ADS Given the nutritional concerns of CR and fasting in some cancer patients, CR mimetics, namely pharmacological agents that target pathways affected by CR, such as rapamycin, metformin, resveratrol, and hydroxycitrate, are attractive strategies to mimic the protective effects of CR both for cancer prevention and as adjuvant therapies without dietary restriction.

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