Preferential interaction with c-MYC quadruplex DNA mediates the cytotoxic activity of a nitro-flavone derivative in A375 cells

The plant flavonoid quercetin (Que) binds more efficiently to VEGF G-quadruplex DNA (G4–DNA) compared to double stranded DNA as well as other G4–DNAs.

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Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity

Dalton Transactions ◽

10.1039/d0dt01527j ◽

2020 ◽

Vol 49 (28) ◽

pp. 9888-9899

Author(s):

Farukh Arjmand ◽

Surbhi Sharma ◽

Sabiha Parveen ◽

Loic Toupet ◽

Zhen Yu ◽

...

Keyword(s):

Cytotoxic Activity ◽

Cell Lines ◽

Cancer Cell ◽

Mtt Assay ◽

Dna Cleavage ◽

Cancer Cell Lines ◽

Cellular Cytotoxicity ◽

Site Specific ◽

Quadruplex Dna ◽

G Quadruplex

Chiral l-/d-valine-(1,10-phen)-Cu(ii) complexes that target G-quadruplex DNA were synthesized and thoroughly characterized. The cytotoxic activity of 1a and 1b on some of the notably important cancer cell lines was evaluated by MTT assay.

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A375 Melanoma Cells are Sensitized to Cisplatin-Induced Toxicity by a Synthetic Nitro-Flavone Derivative 2-(4-Nitrophenyl)-4H-Chromen-4-one Through Inhibition of PARP1

10.21203/rs.3.rs-616350/v1 ◽

2021 ◽

Author(s):

Anindita Mitra ◽

Rita Ghosh

Keyword(s):

Combination Therapy ◽

In Silico ◽

Nuclear Dna ◽

Binding Mode ◽

Melanoma Cells ◽

Parp1 Inhibitors ◽

Flavone Derivative ◽

A375 Melanoma ◽

Isobologram Analysis ◽

A375 Cells

Abstract Background: Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses. Methods and Results: In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD+) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis. Conclusion: The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy.

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Effects of Glutathione Transferase-Targeting Nitrobenzoxadiazole Compounds in Relation to PD-L1 Status in Human Melanoma Cells

Chemotherapy ◽

10.1159/000503339 ◽

2019 ◽

Vol 64 (3) ◽

pp. 138-145

Author(s):

Francesca Sciarretta ◽

Chiara Fulci ◽

Camilla Palumbo ◽

Dante Rotili ◽

Lucio Tentori ◽

...

Keyword(s):

Western Blot ◽

Cytotoxic Activity ◽

Glutathione Transferase ◽

Braf Inhibitor ◽

Melanoma Cells ◽

Lower Sensitivity ◽

Cytotoxic Effects ◽

Autophagy Inhibitor ◽

A375 Melanoma ◽

A375 Cells

Background: PD-L1 is a membrane protein with inhibitory effects on immune responses, whose expression has been correlated with high aggressiveness and the propensity of melanoma to metastasize. The nitrobenzoxadiazole (NBD) NBDHEX and its analog MC3181 are endowed with strong antitumor activity towards melanoma and a significant ability to reduce its adhesion and invasiveness. Therefore, we investigated whether PD-L1 status could affect cell sensitivity to the cytotoxic effects of NBDs. We then evaluated the effects of NBDHEX on PD-L1 expression and autophagy in melanoma cells. We used the BRAF-mutated A375 melanoma cell line and an A375 variant population enriched for PD-L1+ cells as a model. The cytotoxic effects of NBDs were evaluated in comparison to those of the BRAF inhibitor vemurafenib and the autophagy inhibitor chloroquine. Methods: The effect of NBDHEX on autophagy was determined by measuring LC3-II and p62 protein levels by Western blot. The cytotoxic activity of the compounds was evaluated by sulforhodamine B assay. PD-L1 expression and plasma membrane localization were analyzed by FACS and Western blot analysis. Results: NBDHEX behaves as a late-autophagy inhibitor in A375 melanoma cells, as previously found in other tumor cell lines. NBDHEX and MC3181 showed strong and comparable cytotoxic activity in both parental and PD-L1+ A375 cells, with IC50 values in the sub-micromolar range. Conversely, cells sorted for high PD-L1 expression had lower sensitivity to both the BRAF inhibitor vemurafenib and the autophagy inhibitor chloroquine. NBDHEX treatment did not change the total expression and cell surface localization of PD-L1 in both parental and PD-L1+ A375 cells. Conclusions: Our data suggest that NBDs may represent a promising treatment strategy for melanoma with elevated PD-L1 expression.

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