Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

Chiaradonna, Ferdinando; Barozzi, Iros; Miccolo, Claudia; Bucci, Gabriele; Palorini, Roberta; Fornasari, Lorenzo; Botrugno, Oronza A.; Pruneri, Giancarlo; Masullo, Michele; Passafaro, Alfonso; Galimberti, Viviana; Fantin, Valeria R.; Richon, Victoria M.; Pece, Salvatore; Viale, Giuseppe; Fiore, Pier Paolo Di; Draetta, Giulio; Pelicci, Pier Giuseppe; Minucci, Saverio; Chiocca, Susanna

doi:10.1089/ars.2014.6189

Cited by 13 publications

(4 citation statements)

References 78 publications

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“…SAHA inhibits the class I HDACs (HDAC1, HDAC2, HDAC3) and the class II HDACs (HDAC6) and under the trade name Zolinza® was the first histone deacetylase inhibitor approved by FDA for clinical use in cutaneous T cell lymphoma (CTCL) 31, 32. SAHA is a compound with low toxicity in normal cells 33, which was also confirmed in the current study, and high therapeutic potential for different tumors including colon cancer 34, prostate cancer 35, breast cancer 36, non-small cell lung cancer 37, pancreatic cancer 38, glioma cells 39, uterine sarcoma 40, ovarian cancer 41 and oral squamous cell carcinoma 42. In the present study, we showed that SAHA suppressed the growth of larynx cancer cell lines at micromolar concentrations in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 75%

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

et al. 2017

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Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells -primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

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Section: Discussionsupporting

confidence: 75%

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

et al. 2017

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“…As previously illustrated, ROS are considered critical players in anoikis -resistance due to their positive effect on pro-survival cell signaling and tumor metastasis [ 60 ]. However excessive and unmitigated ROS increase can result in cell death [ 102 , 103 , 104 ]. Remarkably, our results indicated that the antioxidant NAC can partially rescue H89-treated detached cells, underscoring the fact the PKA controls an antioxidant response critical for anoikis -resistance.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis

et al. 2016

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Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment.

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“…Suberoylanilide hydroxamic acid (SAHA), also called vorinostat, belongs to the hydroxamic acid class of histone deacetylase (HDAC) inhibitors 7 , 8 . It was shown that SAHA exerted great clinical utility as a therapeutic intervention after intracerebral hemorrhage 9 .…”

Section: Introductionmentioning

confidence: 99%

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

et al. 2022

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Increased focus has been placed on the role of histone deacetylase inhibitors as crucial players in subarachnoid hemorrhage (SAH) progression. Therefore, this study was designed to expand the understanding of SAH by exploring the downstream mechanism of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in SAH. The expression of TDP-43 in patients with SAH and rat models of SAH was measured. Then, western blot analysis, immunofluorescence staining, and transmission electron microscope were used to investigate the in vitro effect of TDP-43 on a neuronal cell model of SAH established by oxyhemoglobin treatment. Immunofluorescence staining and coimmunoprecipitation assays were conducted to explore the relationship among histone deacetylase 1 (HDAC1), heat shock protein 70 (HSP70), and TDP-43. Furthermore, the in vivo effect of HDAC1 on SAH was investigated in rat models of SAH established by endovascular perforation. High expression of TDP-43 in the cerebrospinal fluid of patients with SAH and brain tissues of rat models of SAH was observed, and TDP-43 accumulation in the cytoplasm and the formation of inclusion bodies were responsible for axonal damage, abnormal nuclear membrane morphology, and apoptosis in neurons. TDP-43 degradation was promoted by the HDAC1 inhibitor SAHA via the acetylation of HSP70, alleviating SAH, and this effect was verified in vivo in rat models. In conclusion, SAHA relieved axonal damage and neurological dysfunction after SAH via the HSP70 acetylation-induced degradation of TDP-43, highlighting a novel therapeutic target for SAH.

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Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

Cited by 13 publications

References 78 publications

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

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