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A Potent Inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen Activated Protein (MAP) Kinase Signalling, Quercetin (3, 3', 4', 5, 7-Pentahydroxyflavone) Promotes Cell Death in Ultraviolet (UV)-B-Irradiated B16F10 Melanoma Cells.

Rafiq RA, Quadri A, Nazir LA, Peerzada K, Ganai BA, Tasduq SA - PLoS ONE (2015)

Bottom Line: The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM).Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation.Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF).

View Article: PubMed Central - PubMed

Affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.

ABSTRACT
Ultraviolet (UV) radiation-induced skin damage contributes strongly to the formation of melanoma, a highly lethal form of skin cancer. Quercetin (Qu), the most widely consumed dietary bioflavonoid and well known inhibitor of phosphoinositide 3-kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, has been reported to be chemopreventive in several forms of non-melanoma skin cancers. Here, we report that the treatment of ultraviolet (UV)-B-irradiated B16F10 melanoma cells with quercetin resulted in a dose dependent reduction in cell viability and increased apoptosis. The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM). Promotion of UVB-induced cell death by quercetin was further revealed by cleavage of chromosomal DNA, caspase activation, poly (ADP) ribose polymerase (PARP) cleavage, and an increase in sub-G1 cells. Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation. Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF). Overall, these results suggest the possibility of using quercetin in combination with UVB as a possible treatment option for melanoma in future.

No MeSH data available.


Related in: MedlinePlus

Quercetin promotes UVB-induced cell death.A, structure of quercetin (Qu). B, analysis of cell viability using the MTT assay in B16F10 cells at 24 h post-UVB irradiation. Columns, mean of three experiments; bars, SD. *, P<0.05; **, P<0.01 for control versus treated. C, analysis of cell viability in Hs68 human fibroblast cells at 24 h post-UVB irradiation. D, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu. *, P<0.05; **, P<0.01 for control versus Qu treated. E, analysis of cell viability using the MTT assay in human HaCaT keratinocytes at 24 h post-Qu treatment. F, analysis of cell viability using the MTT assay in Hs68 human fibroblast cells at 24 h post-Qu treatment. G, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. *, P<0.05; **, P<0.01 for control versus treated; #, P<0.05; ##, P<0.01 for UVB-alone treatment versus UVB + Qu treatments. H, analysis of cell viability using the MTT assay in A375 human melanoma cells at 24 h post-Qu treatment. I, analysis of cell viability using the MTT assay in A375 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. J, analysis of cell viability in Hs68 cells treated with Qu and/or UVB for 24 hours.
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pone.0131253.g001: Quercetin promotes UVB-induced cell death.A, structure of quercetin (Qu). B, analysis of cell viability using the MTT assay in B16F10 cells at 24 h post-UVB irradiation. Columns, mean of three experiments; bars, SD. *, P<0.05; **, P<0.01 for control versus treated. C, analysis of cell viability in Hs68 human fibroblast cells at 24 h post-UVB irradiation. D, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu. *, P<0.05; **, P<0.01 for control versus Qu treated. E, analysis of cell viability using the MTT assay in human HaCaT keratinocytes at 24 h post-Qu treatment. F, analysis of cell viability using the MTT assay in Hs68 human fibroblast cells at 24 h post-Qu treatment. G, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. *, P<0.05; **, P<0.01 for control versus treated; #, P<0.05; ##, P<0.01 for UVB-alone treatment versus UVB + Qu treatments. H, analysis of cell viability using the MTT assay in A375 human melanoma cells at 24 h post-Qu treatment. I, analysis of cell viability using the MTT assay in A375 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. J, analysis of cell viability in Hs68 cells treated with Qu and/or UVB for 24 hours.

Mentions: Quercetin (3, 3', 4', 5, 7-pentahydroxyflavone, Fig 1A) is a diphenyl propanoid widely distributed in fruits and vegetables, with an average daily intake of 25–30 mg [18]. Quercetin displays antioxidant, anti-inflammatory, antimetastatic and anticancer activities [19–22]. Further, quercetin shows potent anti-melanoma activity and strongly inhibited murine B16F10 cells lung metastasis in an animal model [23, 24].


A Potent Inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen Activated Protein (MAP) Kinase Signalling, Quercetin (3, 3', 4', 5, 7-Pentahydroxyflavone) Promotes Cell Death in Ultraviolet (UV)-B-Irradiated B16F10 Melanoma Cells.

Rafiq RA, Quadri A, Nazir LA, Peerzada K, Ganai BA, Tasduq SA - PLoS ONE (2015)

Quercetin promotes UVB-induced cell death.A, structure of quercetin (Qu). B, analysis of cell viability using the MTT assay in B16F10 cells at 24 h post-UVB irradiation. Columns, mean of three experiments; bars, SD. *, P<0.05; **, P<0.01 for control versus treated. C, analysis of cell viability in Hs68 human fibroblast cells at 24 h post-UVB irradiation. D, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu. *, P<0.05; **, P<0.01 for control versus Qu treated. E, analysis of cell viability using the MTT assay in human HaCaT keratinocytes at 24 h post-Qu treatment. F, analysis of cell viability using the MTT assay in Hs68 human fibroblast cells at 24 h post-Qu treatment. G, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. *, P<0.05; **, P<0.01 for control versus treated; #, P<0.05; ##, P<0.01 for UVB-alone treatment versus UVB + Qu treatments. H, analysis of cell viability using the MTT assay in A375 human melanoma cells at 24 h post-Qu treatment. I, analysis of cell viability using the MTT assay in A375 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. J, analysis of cell viability in Hs68 cells treated with Qu and/or UVB for 24 hours.
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pone.0131253.g001: Quercetin promotes UVB-induced cell death.A, structure of quercetin (Qu). B, analysis of cell viability using the MTT assay in B16F10 cells at 24 h post-UVB irradiation. Columns, mean of three experiments; bars, SD. *, P<0.05; **, P<0.01 for control versus treated. C, analysis of cell viability in Hs68 human fibroblast cells at 24 h post-UVB irradiation. D, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu. *, P<0.05; **, P<0.01 for control versus Qu treated. E, analysis of cell viability using the MTT assay in human HaCaT keratinocytes at 24 h post-Qu treatment. F, analysis of cell viability using the MTT assay in Hs68 human fibroblast cells at 24 h post-Qu treatment. G, analysis of cell viability using the MTT assay in B16F10 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. *, P<0.05; **, P<0.01 for control versus treated; #, P<0.05; ##, P<0.01 for UVB-alone treatment versus UVB + Qu treatments. H, analysis of cell viability using the MTT assay in A375 human melanoma cells at 24 h post-Qu treatment. I, analysis of cell viability using the MTT assay in A375 cells treated with Qu and/or UVB (5 mJ/cm2) for 24 hours. J, analysis of cell viability in Hs68 cells treated with Qu and/or UVB for 24 hours.
Mentions: Quercetin (3, 3', 4', 5, 7-pentahydroxyflavone, Fig 1A) is a diphenyl propanoid widely distributed in fruits and vegetables, with an average daily intake of 25–30 mg [18]. Quercetin displays antioxidant, anti-inflammatory, antimetastatic and anticancer activities [19–22]. Further, quercetin shows potent anti-melanoma activity and strongly inhibited murine B16F10 cells lung metastasis in an animal model [23, 24].

Bottom Line: The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM).Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation.Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF).

View Article: PubMed Central - PubMed

Affiliation: PK-PD and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.

ABSTRACT
Ultraviolet (UV) radiation-induced skin damage contributes strongly to the formation of melanoma, a highly lethal form of skin cancer. Quercetin (Qu), the most widely consumed dietary bioflavonoid and well known inhibitor of phosphoinositide 3-kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, has been reported to be chemopreventive in several forms of non-melanoma skin cancers. Here, we report that the treatment of ultraviolet (UV)-B-irradiated B16F10 melanoma cells with quercetin resulted in a dose dependent reduction in cell viability and increased apoptosis. The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM). Promotion of UVB-induced cell death by quercetin was further revealed by cleavage of chromosomal DNA, caspase activation, poly (ADP) ribose polymerase (PARP) cleavage, and an increase in sub-G1 cells. Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation. Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF). Overall, these results suggest the possibility of using quercetin in combination with UVB as a possible treatment option for melanoma in future.

No MeSH data available.


Related in: MedlinePlus