Synergistic enhancement of antitumor effect of β-Lapachone by photodynamic induction of quinone oxidoreductase (NQO1)

Lamberti, María Julia; Vittar, Natalia Belén Rumie; Silva, Fernando de Carvalho da; Ferreira, Vı́tor F.; Rivarola, Viviana

doi:10.1016/j.phymed.2013.04.018

Cited by 42 publications

(30 citation statements)

References 28 publications

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“…Cell viability was evaluated by 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay, which is reduced by mitochondrial dehydrogenases of viable cells to non water-soluble violet formazan crystals [18]. Twenty four hours post-PDT, MTT solution (5mg/ml in phosphate buffer saline, PBS) was added for 4 h (dilution rate: 1/10).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy

et al. 2017

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Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.

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Section: Methodsmentioning

confidence: 99%

Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy

et al. 2017

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“…To better understand the ns-TR 3 spectra variation in the different solutions, DFT calculations have been employed to optimize the structures and predict normal Raman spectra of β-3 LA and α-3 LA. The optimized structures of β-3 LA and α-3 LA are displayed in Figure 10S 15 and CO stretch of C 1 −O 10 and C 2 −O 9 will shift up to higher wavenumber when β-3 LA converts into α-3 LA. This is consistent with the ns-TR 3 experimental Raman spectra changes.…”

Section: The Journal Of Organic Chemistrymentioning

confidence: 99%

Photoconversion of β-Lapachone to α-Lapachone via a Protonation-Assisted Singlet Excited State Pathway in Aqueous Solution: A Time-Resolved Spectroscopic Study

Zhang

et al. 2015

J. Org. Chem.

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The photophysical and photochemical reactions of β-lapachone were studied using femtosecond transient absorption, nanosecond transient absorption, and nanosecond time-resolved resonance Raman spectroscopy techniques and density functional theory calculations. In acetonitrile, β-lapachone underwent an efficient intersystem crossing to form the triplet state of β-lapachone. However, in water-rich solutions, the singlet state of β-lapachone was predominantly quenched by the photoinduced protonation of the carbonyl group at the β position (O9). After protonation, a series of fast reaction steps occurred to eventually generate the triplet state α-lapachone intermediate. This triplet state of α-lapachone then underwent intersystem crossing to produce the ground singlet state of α-lapachone as the final product. 1,2-Naphthoquinone is examined in acetonitrile and water solutions in order to elucidate the important roles that water and the pyran ring play during the photoconversion from β-lapachone to α-lapachone. β-Lapachone can also be converted to α-lapachone in the ground state when a strong acid is added to an aqueous solution. Our investigation indicates that β-lapachone can be converted to α-lapachone by photoconversion in aqueous solutions by a protonation-assisted singlet excited state reaction or by an acid-assisted ground state reaction.

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“…Spheroid viability was evaluated by 1-[4,5-dimethylthiazol-2-yl]-3,5-diphenylformazan (MTT) assay, which is reduced by mitochondrial dehydrogenases of viable cells to nonwatersoluble violet formazan crystals [20]. Twenty-four hours post-PDT, 100-μL MTT solution (5 mg/mL in phosphate buffer saline (PBS)) was added per ten spheroids and incubated for 4 h. Then, dimethyl sulfoxide (DMSO) was added to lyse the cells and solubilize the precipitated formazan product.…”

Section: Spheroid Viability Assaymentioning

confidence: 99%

Contribution of resident and recruited macrophages to the photodynamic intervention of colorectal tumor microenvironment

et al. 2015

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The study of cellular interactions in the tumor microenvironment has become one of the main areas of research in the fight against cancer. Tumor-associated macrophages (TAMs) influence tumor progression and therapy response due to its functional plasticity. Regarding cancer treatment, photodynamic therapy (PDT) is a minimally invasive and clinically approved procedure that involves the administration of a photosensitizer (PS), a nontoxic photosensitizing drug which is selectively retained in neoplastic tissue. Here, we investigated the role of resident and nonresident macrophages in the context of a PDT-treated colorectal tumor by developing a combination of 2-D and three-dimensional (3-D) experimental platform, recreating tumor-stroma interactions in vitro. Enhancement of cytotoxicity of PDT was achieved in the presence of nonresident macrophages which had a strong anti-tumor phenotype mediated by the production of nitric oxide, IL-6, and tumor necrosis factor alpha (TNF-α). On the contrary, tumor resident macrophages induced a pro-tumor phenotype promoting tumor cell migration and endothelial stimulation. Due to their plasticity, tumor-resident or tumor-recruited macrophages can differentially influence the response of tumors to PDT, so their multifactorial roles should be considered in the overall design of anti-tumor therapeutic.

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Synergistic enhancement of antitumor effect of β-Lapachone by photodynamic induction of quinone oxidoreductase (NQO1)

Cited by 42 publications

References 28 publications

Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy

Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy

Photoconversion of β-Lapachone to α-Lapachone via a Protonation-Assisted Singlet Excited State Pathway in Aqueous Solution: A Time-Resolved Spectroscopic Study

Contribution of resident and recruited macrophages to the photodynamic intervention of colorectal tumor microenvironment

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