Melanoma cells replicate through chemotherapy by reducing levels of key homologous recombination protein RAD51 and increasing expression of translesion synthesis DNA polymerase ζ

Song, Liang; McNeil, Ewan M.; Ritchie, Ann-Marie; Astell, Katy R.; Gourley, Charlie; Melton, David W.

doi:10.1186/s12885-017-3864-6

Cited by 10 publications

(8 citation statements)

References 41 publications

(48 reference statements)

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“…In addition, in line with previous reports we observed that enforced miR-204-5p expression was also able to inhibit the expression levels of RAD51, FOXM1 and NOTCH1 [18] (Supplementary Fig. S3B) [25–27]. Moreover, MAPKi-resistant melanoma cells consistently underwent a prominent increase of endogenous NOTCH1 levels and a cell-type dependent increase of the other two miR-204-5p targets RAD51 and FOXM1 (Supplementary Fig.…”

Section: Resultssupporting

confidence: 89%

Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

et al. 2018

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Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis. Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence. Targeting these alterations blunts the development of drug resistance.

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Section: Resultssupporting

confidence: 89%

Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

et al. 2018

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“…Our earlier result showed that the IC 50 value of cisplatin treatment was reduced by ~ 2 fold with ACPH in A375 cells [5]. Olaparib, another PARP1 inhibitor decreased the IC 50 value of cisplatin by ~ 5 fold in A375 cells [35]. For combined treatment with cisplatin and 4NCO in A375 cells, the fold reduction IC 50 was found to be ~ 12 fold at some concentrations chosen for the study, which indicated that 4NCO was much more productive in potentiating the sensitivity to cisplatin-induced killing.…”

Section: Discussionmentioning

confidence: 99%

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

Mitra

Ghosh

2021

Mol Biol Rep

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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 e cacy at lower doses.Methods and Results: In this work, we have shown that the nitro-avone 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 con rmed 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-avone 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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“…10,43,44 Interestingly, we noticed that although combined treatment with JQ1 and HDACIs robustly abolished the expression of endogenous RAD51, the expression of exogenous HA-RAD51 (under a CMV promoter) was essentially unaffected. RAD51 expression can be regulated via transcription, miRNAs including miR-96, −99, −107, −222 and −155, and protein stability, 45 further studies are warranted to disclose the detailed regulatory mechanism of JQ1 combined with HDACIs in regulating RAD51 expression in chondrosarcoma.…”

Section: Discussionmentioning

confidence: 99%

<p>Combination BET Family Protein and HDAC Inhibition Synergistically Elicits Chondrosarcoma Cell Apoptosis Through RAD51-Related DNA Damage Repair</p>

Huan¹,

Gui²,

Xu³

et al. 2020

CMAR

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Background: Chondrosarcoma is the second-most common type of bone tumor and has inherent resistance to conventional chemotherapy. Present study aimed to explore the therapeutic effect and specific mechanism(s) of combination BET family protein and HDAC inhibition in chondrosarcoma. Methods: Two chondrosarcoma cells were treated with BET family protein inhibitor (JQ1) and histone deacetylase inhibitors (HDACIs) (vorinostat/SAHA or panobinostat/PANO) separately or in combination; then, the cell viability was determined by Cell Counting Kit-8 (CCK-8) assay, and the combination index (CI) was calculated by the Chou method; cell proliferation was evaluated by 5-ethynyl-2′-deoxyuridine (EdU) incorporation and colony formation assay; cell apoptosis and reactive oxygen species (ROS) level were determined by flow cytometry; protein expressions of caspase-3, Bcl-XL, Bcl-2, γ-H2AX, and RAD51 were examined by Immunoblotting; DNA damage was determined by comet assay; RAD51 and γ-H2AX foci were observed by immunofluorescence. Results: Combined treatment with JQ1 and SAHA or PANO synergistically suppressed the growth and colony formation ability of the chondrosarcoma cells. Combined BET and HDAC inhibition also significantly elevated the ROS level, followed by the activation of cleaved-caspase-3, and the downregulation of Bcl-2 and Bcl-XL. Mechanistically, combination treatment with JQ1 and SAHA caused numerous DNA double-strand breaks (DSBs), as evidenced by the comet assay. The increase in γ-H2AX expression and foci formation also consistently indicated the accumulation of DNA damage upon cotreatment with JQ1 and SAHA. Furthermore, RAD51, a key protein of homologous recombination (HR) DNA repair, was found to be profoundly suppressed. In contrast, ectopic expression of RAD51 partially rescued SW 1353 cell apoptosis by inhibiting the expression of cleaved-caspase-3. Conclusion: Taken together, our results disclose that BET and HDAC inhibition synergistically inhibit cell growth and induce cell apoptosis through a mechanism that involves the suppression of RAD51-related HR DNA repair in chondrosarcoma cells.

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Melanoma cells replicate through chemotherapy by reducing levels of key homologous recombination protein RAD51 and increasing expression of translesion synthesis DNA polymerase ζ

Cited by 10 publications

References 41 publications

Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

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

<p>Combination BET Family Protein and HDAC Inhibition Synergistically Elicits Chondrosarcoma Cell Apoptosis Through RAD51-Related DNA Damage Repair</p>

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