Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

Bravo-Cuéllar, Alejandro; Ortiz‐Lazareno, Pablo César; Sierra-Díaz, Erick; Solorzano‐Ibarra, Fabiola; Méndez-Clemente, Anibal Samael; Aguilar‐Lemarroy, Adriana; Jave‐Suárez, Luis Felipe; Velazco-Niño, Édgar Ruiz; Hernández‐Flores, Georgina

doi:10.3389/fonc.2020.592706

Cited by 14 publications

(8 citation statements)

References 44 publications

(57 reference statements)

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“…Our results suggest that the regulation of miR27a by the p38 pathway may occur at the transcriptional level, but the direct regulatory factors have not been found yet, and we will further explore it in future studies. However, although NF‐κB has been reported to be involved in many biological processes in many literatures, 47 , 48 our results show that NFκB inhibitors only increase the expression of the precursor miR27a, but have no significant effect on miR27a, this may be due to the shear and degradation of the precursor miR27a. Interestingly, TNF‐α is an important factor in disc degeneration 49 , 50 ; thus, these results suggest that TNF‐α induces apoptosis, the inflammatory response and extracellular matrix degradation and promotes FSTL1 expression when IDD occurs.…”

Section: Discussioncontrasting

confidence: 57%

TNF‐α induces up‐regulation of MicroRNA‐27a via the P38 signalling pathway, which inhibits intervertebral disc degeneration by targeting FSTL1

Shi

Wang

et al. 2021

J Cellular Molecular Medi

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The mechanism of intervertebral disc degeneration is still unclear, and there are no effective therapeutic strategies for treating this condition. miRNAs are naturally occurring macromolecules in the human body and have many biological functions. Therefore, we hope to elucidate whether miRNAs are associated with intervertebral disc degeneration and the underlying mechanisms involved. In our study, differentially expressed miRNAs were predicted by the GEO database and then confirmed by qPCR and in situ hybridization. Apoptosis of nucleus pulposus cells was detected by flow cytometry and Bcl2, Bax and caspase 3. Deposition of extracellular matrix was assessed by Alcian blue staining, and the expression of COX2 and MMP13 was detected by immunofluorescence, Western blot and qPCR. Moreover, qPCR was used to detect the expression of miR27a and its precursors. The results showed that miR27a was rarely expressed in healthy intervertebral discs but showed increased expression in degenerated intervertebral discs. Ectopic miR27a expression inhibited apoptosis, suppressed the inflammatory response and attenuated the catabolism of the extracellular matrix by targeting FSTL1. Furthermore, it seems that the expression of miR27a was up‐regulated by TNF‐α via the P38 signalling pathway. So we conclude that TNF‐α and FSTL1 engage in a positive feedback loop to promote intervertebral disc degeneration. At the same time, miR27a is up‐regulated by TNF‐α via the P38 signalling pathway, which ameliorates inflammation, apoptosis and matrix degradation by targeting FSTL1. Thus, this negative feedback mechanism might contribute to the maintenance of a low degeneration load and would be beneficial to maintain a persistent chronic disc degeneration.

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Section: Discussioncontrasting

confidence: 57%

TNF‐α induces up‐regulation of MicroRNA‐27a via the P38 signalling pathway, which inhibits intervertebral disc degeneration by targeting FSTL1

Shi

Wang

et al. 2021

J Cellular Molecular Medi

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“…As shown in Figure 4A , the therapeutic effect of DDP on A2780/DDP cells was significantly reduced (IC 50 = 10.91 × 0.67 ppm), whereas that on parental A2780 cells remained sensitive (IC 50 = 1.94 × 0.17 ppm). According to previous studies, resistant cells generally upregulate intracellular GSH to inactivate DDP with GS-Pt adducts ( Levy et al, 2019 ; Bravo-Cuellar et al, 2020 ; Xu et al, 2020 ). As shown in Figure 4B , A2780/DDP cells were characterized by higher expression levels of GSH similar to those previously reported ( Xu et al, 2020 ).…”

Section: Resultsmentioning

confidence: 96%

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

Wang

et al. 2022

Front. Chem.

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Cisplatin (also known as DDP) resistance is one of the biggest challenges in the treatment of ovarian cancer. Recent studies have found that mitochondrion, as a potential target of DDP, participates in drug-related apoptosis and resistance. Overexpressed glutathione (GSH) in resistant cells is involved in protecting mitochondria from DDP or DDP-induced ROS. In this work, triphenylphosphonium (TPP) modified disulfide bond-rich (S-S) mesoporous organic silica nanoplatforms (DMON) were developed to deliver DDP (TPP-DMON@DDP) to mitochondria for overcoming DDP resistance. TPP supported the migration of nanoplatforms to the mitochondria, with consequent depletion of mitochondrial GSH by the S-S bond of DMON, leading to mitochondria in redox dyshomeostasis. These treated cells seemed more susceptible to the DDP released from the nanoplatforms. Significantly increased ROS production, mitochondrial damage, and apoptosis were observed in TPP-DMON@DDP-treated cells. Overall, interference of mitochondrial redox homeostasis provides a new opportunity for improving DDP cytotoxicity against resistant cells.

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“…The results showed that differentially expressed genes were mainly enriched in the NF-κB signaling pathway. A previous study has found that adding carboplatin to cervical cancer SiHa and CaSki cells can activate the NF-κB signaling pathway and induce the expression of NF-κB ( 27 ). Our Western blot results also found that in EOC carboplatin-resistant cells, the nuclear expression of NF-κB p65 was significantly increased, and the expression of IκBα was significantly reduced, indicating that the up-regulation of NF-κB may inhibit EOC carboplatin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

Li¹,

Zhou²,

Shen³

et al. 2021

Transl Cancer Res TCR

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Background: The incidence of ovarian cancer ranks third among female gynecological cancers in the world, and more than 90% of patients are epithelial ovarian cancer (EOC). Carboplatin is the first-line chemotherapy drug for the treatment of EOC patients. However, patients who are resistant to carboplatin often do not benefit from it. Therefore, finding a key molecule that affects carboplatin sensitivity is expected to enhance the efficacy of carboplatin in EOC treatment. Methods:The human EOC cell line SK-OV-3 and TOV-21G were used in this study. The secondgeneration sequencing technology was used to sequence the transcripts of carboplatin-resistant EOC cells and parental EOC cells. The bioinformatic analysis of the differentially expressed genes was performed by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.The EOC tissue chip in the Gene Expression Omnibus (GEO) database was also analyzed to screen the target gene. Flow cytometry, Hoechst staining, Western blot, MTS, mitochondrial specific reducing agent (Mito Tempo), and nuclear factor kappa-B (NF-κB) pathway inhibitor (BAY 11-7082) were used to explore the effect of proteasome 26S subunit, non-ATPase 4 (PSMD4) on the autophagy, apoptosis, and reactive oxygen species (ROS) accumulation of carboplatin-resistant EOC cells treated with carboplatin. In vivo, the carboplatin-resistant EOC cell lines treated with PSMD4 knockdown were injected subcutaneously into mice (twelve female BALB/c nude mice) to construct EOC subcutaneous xenograft tumor models.Results: Based on second-generation sequencing technology and bioinformatics analysis, it was found that PSMD4 is the core molecule in the carboplatin resistance regulatory network in EOC, and its expression is up-regulated in EOC carboplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the down-regulated expression of PSMD4 is closely related to the increase in sensitivity of EOC to carboplatin. Mechanically, we found that inhibiting PSMD4 expression may inhibit the activation of the NF-κB pathway, promote carboplatin-induced ROS accumulation in EOC cells, inhibit EOC cell autophagy, and enhance the sensitivity of EOC to carboplatin.

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Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

Cited by 14 publications

References 44 publications

TNF‐α induces up‐regulation of MicroRNA‐27a via the P38 signalling pathway, which inhibits intervertebral disc degeneration by targeting FSTL1

TNF‐α induces up‐regulation of MicroRNA‐27a via the P38 signalling pathway, which inhibits intervertebral disc degeneration by targeting FSTL1

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

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