An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G2/M-phase arrest in mammary adenocarcinoma TA3

Urra, Félix A.; Martínez-Cifuentes, Maximiliano; Pavani, Mario; Lapier, Michel; Jaña, Fabián; Parra, Eduardo; Maya, Juan Diego; Pessoa‐Mahana, Hernán; Ferreira, Jorge; Araya‐Maturana, Ramiro

doi:10.1016/j.taap.2012.12.023

Cited by 30 publications

(31 citation statements)

References 48 publications

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“…19 Recently, they reported the anti-tumor mechanism of an ortho -carbonyl substituted hydroquinone, 9,10-dihydroxyl-4,4-dimethyl-1,4,5,8-tetrahydroanthracen-1-one, which inhibit mitochondrial bioenergetics. 21 We tested compounds 3, 4 and 7 , however, compound 4 generated insoluble crystals when added to the cell culture medium (aqueous environment) and was not analyzed further. The human CEM cell line was found to be more sensitive to the experimental compounds among the other cell lines and was selected to perform more rigorous cell death and apoptosis experiments.…”

Section: Resultsmentioning

confidence: 99%

“…18,19 Most recently, a tricyclic compounds, 9,10-dihydroxy-4,4-dimethyl-1,4,5,8-tetrahydroanthracen-1-one, was found to block the electron flow through the NADH dehydrogenase leading to inhibition of mitochondrial bioenergetics and induction of G2/M-phase arrest. 21 The results of cytotoxicity study indicated that the activity of cell growth inhibition increases with the increase in free radical stability. 18 They also mentioned that cell penetration resulting from the lipophilicity of the compounds contributed to the inhibition in cell growth.…”

Section: Introductionmentioning

confidence: 99%

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The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

Pedroza

León

Varela-Ramı́rez

et al. 2014

Bioorganic & Medicinal Chemistry

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Here, we tested seven 2-acylated-1,4-hydronaphthoquinones for their cytotoxic effects on a panel of cancer lymphoma/leukemia cells and compared to a non-cancer origin cell line. Several naphthohydroquinones exhibited selective cytotoxic effects on lymphoma/leukemia cells with lowest activity on non-cancer cells. The mode of cell death induced by an acylated naphthohydroquinone, which has a long alkyl chain, was found to be via apoptosis. Furthermore, the naphthohydroquinone provoked mitochondria depolarization and activation of its downstream effector, caspase-3, thus implicating the intrinsic apoptotic pathway as its mechanism to exert cell death.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

Pedroza

León

Varela-Ramı́rez

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Previously, we described an anti-cancer ortho -carbonyl substituted hydroquinone scaffold 55 that through small structural changes determines three types of compounds with mitochondrial action 26 . One of these types corresponds to compounds with dual action (inhibitors of complex I-dependent respiration and uncouplers of OXPHOS) whose ester derivatives and benzophenone, chromone and benzofuran scaffolds were used to screen the effect on these cells.…”

Section: Discussionmentioning

confidence: 99%

“…The MTT assay was used to evaluate cellular proliferation as described previously 55 . Briefly, 1 × 10 4 cells/100 µL were seed in 96-well microtiter plates and incubated in either +glu/+gln or −glu/+gln media for 24 h. The cells were then treated during 48 h with increasing concentrations of ortho -carbonyl compounds, mitochondriotoxic and glycolytic drugs to obtain a dose-response curve and obtaining the IC 50 values in both conditions.…”

Section: Methodsmentioning

confidence: 99%

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FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

Urra

Muñoz

Córdova-Delgado

et al. 2018

Sci Rep

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Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

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Thermodynamics and ²H NMR Study on the Insertion of Small Quinones into a Discotic Nematic Lyotropic Liquid Crystal

et al. 2014

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A detailed description of the distribution, interaction, and dynamics of molecules with biological activity dissolved in a hydrophobic bilayer, a simple model of a biological membrane, provides valuable information for a better understanding of drug functioning, which can be very useful in drug design. Here we present an (2)H NMR and molecular dynamics study on the insertion, distribution, interactions, and thermodynamics of two biologically active molecules, 9,10-dihydroxy-4,4-dimethyl-1,4,5,8-tetrahydroanthracen-1-one (HQ), with anticancer activity, and 4,4-dimethyl-1,4,5,8,9,10-hexahydroanthracen-1,9,10-trione (Q) a fungicide, dissolved in a nematic discotic lyotropic liquid crystal (ndllc) composed of sodium dodecylsulphate (SDS), decanol (DecOH) and Na2 SO4 in water. (2)H NMR quadrupole splittings (ΔνQ ) and longitudinal relaxation times (T1) from HQ-d6, Q-d4, DecOH-α-d2, partially deuterated water, and SDS-d25 were measured and several molecular dynamics trajectories were also calculated. In particular, ΔG, ΔH, and ΔS profiles for the process of both molecules crossing the bilayer were estimated. It was evidenced that the insertion of both molecules into the aggregate is a spontaneous process, and the molecules are mainly distributed in the internal side of the interface. Addition of HQ or Q decreased the mobility of all aggregate components, but this effect was more pronounced for HQ. The rotational correlation time of Q allowed an estimate of 5.3 cP for the microviscosity inside the ndllc aggregate, in the order of previously measured values in similar environments. Both guest molecules display similar free-energy profiles for the process of crossing the bilayer, with a calculated barrier height of 25 and 36 kJ mol(-1) for HQ and Q, respectively.

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An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G2/M-phase arrest in mammary adenocarcinoma TA3

Cited by 30 publications

References 48 publications

The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

Thermodynamics and ²H NMR Study on the Insertion of Small Quinones into a Discotic Nematic Lyotropic Liquid Crystal

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An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G2/M-phase arrest in mammary adenocarcinoma TA3

Cited by 30 publications

References 48 publications

The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

Thermodynamics and 2H NMR Study on the Insertion of Small Quinones into a Discotic Nematic Lyotropic Liquid Crystal

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Thermodynamics and ²H NMR Study on the Insertion of Small Quinones into a Discotic Nematic Lyotropic Liquid Crystal