Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia

Shahrzad, Siranoush; Lacombe, Kristen; Adamcic, Una; Minhas, Kanwal; Coomber, Brenda L.

doi:10.1016/j.canlet.2010.04.027

Cited by 50 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DADA, with enhanced lipid solubility, exhibited stronger cytotoxicity than DCA in vitro ( Figure S1). The apoptosis rates obtained from flow cytometry analysis further illustrated that both DCA and DADA induced minor apoptosis in C26 cells, even at a 25 mM concentration ( Figure S2), consistent with a previous report (Shahrzad et al, 2010). Additionally, a cell morphology analysis revealed necrotic features of tumor cells exposed to DCA or DADA therapy in vitro or in vivo ( Figure S3).…”

Section: Resultssupporting

confidence: 89%

“…The above results indicate that the DCA-loaded mat obtained a tumor suppression rate of 75% in less than two weeks, even with an initial tumor volume of 300 mm 3 , which clarifies the paradox of DCA's anti-tumor activity observed in the oral studies of colorectal cancer (Shahrzad et al, 2010;SanchezArago et al, 2011). Meanwhile, after 15 d treatment of DADA-loaded mats, a 95% tumor suppression rate without any relapse phenomenon was achieved (Figure 1).…”

Section: Discussionsupporting

confidence: 58%

“…The opposing findings have mainly arisen from the most studied colorectal cancer model. Some researchers observed a growth inhibition of colorectal cancer in vitro and in vivo (Madhok et al, 2010;Babu et al, 2011;SanchezArago et al, 2011) or a synergistic anti-tumor effect of DCA with other anti-tumor agents (Xiao et al, 2010;Tong et al, 2011;Ishiguro et al, 2012), while others observed no growth inhibition but rather an enhancement of the tumor (Cairns et al, 2007(Cairns et al, , 2009Shahrzad et al, 2010;Yaromina et al 2012). These recent findings have revealed an apparent paradox in the anti-cancer activity of DCA, which therefore, requires further verification prior to its application for tumor therapy.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

et al. 2013

View full text Add to dashboard Cite

Differences in energy metabolism between tumor cells and normal cells offer an attractive avenue of research into drug targets for tumor therapy. The use of a metabolic modulator (sodium dichloroacetate, DCA), administered in situ, to reverse the ''Warburg effect'' of tumor cells has been demonstrated as an effective tumor therapy. Herein, DCA and diisopropylamine dichloroacetate (DADA) were incorporated separately into polylactide (PLA) electrospun mats and applied to C26 tumor-bearing mice via in situ administration. After 12 d of treatment, the tumor suppression rates of 75% and 84% were achieved in the DC group (treated with a DCA-loaded mat) and the DA group (treated with a DADA-loaded mat), respectively. With tolerable physiologic toxicity under high local concentration, the DA group showed a 95% tumor suppression rate without any recurrence after 15 d of therapy. The desirable therapeutic effects of these metabolic modulators should ascribe to the energy-central metabolismtargeting effects of DCA and DADA, which were demonstrated both in vitro and in vivo. Therefore, DCA-and DADA-loaded mats are the effective anti-cancer drugs dosages to discriminate between tumor cells and normal cells for minimizing systemic toxicity. KeywordsColorectal cancer, diisopropylamine dichloroacetate (DADA), electrospun mats, metabolism targeting, sodium dichloroacetate (DCA) History

show abstract

Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Our study demonstrated that not all cell lines were susceptible to DCA-induced cell death to the same degree of sensitivity. We have also confirmed that DCA induces apoptotic effects at least at lower doses, as previously reported by other researchers [6] [18] [21]. Our data demonstrated that the aggressive cancerous cells MCF-7, was more sensitive to DCA than less aggressive MC3T3.…”

Section: Discussionsupporting

confidence: 92%

Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

Al-Karakooly¹,

Kilaparty²,

Al-Anbaky³

et al. 2014

JCT

View full text Add to dashboard Cite

Cancer cells utilize cytosolic glycolysis for their energy production even in the presence of adequate levels of oxygen (Warbug effect) due to mitochondrial defects. Dichloroacetic acid (DCA) shifts cytosolic glucose metabolism to aerobic oxidation by inhibiting mitochondrial pyruvate dehydrogenase kinase (PDK) and increasing pyruvate uptake. Therefore, DCA has potential in reversing the glycolytic metabolism defect in cancerous cells. DCA is also known to induce apoptosis in a number of cancer cell lines, the mechanism of which is not well understood. In this study, an attempt has been made to investigate the effects of DCA on aggressive human breast cancer (MCF-7) cells as compared with less aggressive mouse osteoblastic (MC3T3) cells. Cell cytotoxicity was determined by MTT, crystal violet and Trypan blue exclusion assays. Western blot was used to detect any changes in the expression of apoptotic markers. Flow cytometry was used to measure apoptotic and necrotic effects of DCA. Mitochondrial integrity was determined by change in mitochondrial membrane potential (Δψm), whereas oxidative damage was determined by production * Corresponding author. Z. Alkarakooly et al. 1235of reactive oxygen species (ROS). DCA caused a concentration-dependent cytotoxicity both in MCF-7 and MC3T3 cell lines. MCF-7 cells were most affected. Flow cytometry results showed a significantly higher apoptosis in MCF-7 even at lower concentrations of DCA. However, higher concentrations of DCA were necrotic. Western blotting showed an increased expression of Mn-SOD-1 upon DCA treatment. Further, DCA decreased Δψm and increased ROS production. The effects of DCA were more pronounced on MCF-7 cells as compared to MC3T3 cells. Our results suggest that DCA-induced cytotoxicity in cancerous cells is mediated via changes in Δψm and production of ROS.

show abstract

“…На основании этих результатов авторы предполагают, что такая ком-бинация может повысить эффективность терапии за счет потенцирования действия химиотерапев-тических препаратов [54]. Третье исследование посвящено изучению влияния гипоксии на апоптоз клеток колоректального рака in vitro и in vivo [40]. НДХА действительно вызывает выраженный апоп-тоз этих клеток в условиях нормоксии, но при ги-поксии он уменьшается, что приводит к усилению роста опухолевого ксенотрансплантата в частях новообразований, подвергшихся гипоксическому влиянию.…”

Section: рак толстого кишечникаunclassified

The Biological Activity of Sodium Dichloroacetate and Its Effectiveness During the Experimental Clinical Studies

Цымбалюк¹,

Мануйлов²,

Popov³

et al. 2017

Kuban. nauсh. med. vestnik

View full text Add to dashboard Cite

15123. Mizutani N., Sakurai T., Shibata T. et al. Dose-dependent differential regulation of cytokine secretion from macrophages by Fractalkine // Immunol. -2007. -Vol. 179, № 11. -P. 7478-7487. 24. Pachot A., Cazalis M.A., Venet F. et России, Россия, 350063, г. Краснодар, ул. Седина, 4; 3 эндокринологическое отделение МБУЗ ГКБ № 1, Россия, 350000, г. Краснодар, ул. Красная 103/Длинная 123; тел. +7 (928) 430-07-69. E-mail: igor_ts@inbox.ru Исследованию биологической активности дихлорацетата натрия посвящено более 1400 работ в зарубежных из-даниях. Между тем в отечественной литературе представленный обзор является первым и имеет цель объединить и систематизировать результаты многочисленных исследований его эффектов in vitro, на разнообразных клеточ-ных линиях, экспериментальных моделях, а также на целостном организме при широком спектре патологических состояний и заболеваний, сопровождающихся митохондриальной дисфункцией. Механизм его действия связан с активацией пируватдегидрогеназного комплекса, результатом чего в нормальных клетках, находящихся в условиях тканевой гипоксии, является оптимизация расходования кислорода и снижение уровня ацидификации среды, что позволяет относить его к метаболическим цитопротекторам. В атипичных же клетках результатом этого является инверсия метаболизма с интенсификацией свободнорадикальных процессов, активацией каспазного ферментного каскада, снижением активности пропролиферативных и проангиогенетических транскрипционных факторов, что объясняет позитивный эффект в лечении целого ряда опухолей.Ключевые слова: дихлорацетат натрия, митохондриальная дисфункция, пируватдегидрогеназа, метаболиче-ская цитопротекция, противоопухолевая терапия.

show abstract

Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia

Cited by 50 publications

References 46 publications

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

The Biological Activity of Sodium Dichloroacetate and Its Effectiveness During the Experimental Clinical Studies

Contact Info

Product

Resources

About