FK228 sensitizes radioresistant small cell lung cancer cells to radiation

Li, Hong; Ma, Liying; Bian, Xiaoying; Lv, Yang; Lin, Wenchu

doi:10.1186/s13148-021-01025-5

Cited by 12 publications

(11 citation statements)

References 31 publications

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“…This is in line with earlier published data by Jin et al [ 19 ] who showed a slightly increased radiosensitivity upon treatment of BON-1 and QGP-1 cells with CI-994. Similar results were demonstrated for several other cancer types [ 30 , 31 , 32 , 33 ]. This suggests that VPA may have a dual function; it increases both SSTR2 mRNA expression levels and uptake of [ 111 In]In-DOTATATE, and it increases radiosensitivity towards PRRT.…”

Section: Discussionsupporting

confidence: 87%

Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [111In]In-DOTATATE Uptake in NET Cells

Klomp

Dalm

Koetsveld

et al. 2021

Cancers

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The aim of this study was to increase somatostatin type-2 receptor (SSTR2) expression on neuroendocrine tumor (NET) cells using histone deacetylase inhibitors (HDACis), potentially increasing the uptake of SSTR2-targeted radiopharmaceuticals and subsequently improving treatment efficacy of peptide receptor radionuclide therapy (PRRT). Human NET cell lines BON-1, NCI-H727, and GOT1 were treated with HDACis (i.e., CI-994, entinostat, LMK-235, mocetinostat, panobinostat, or valproic acid (VPA); entinostat and VPA were the HDACis tested in GOT1 cells) to examine SSTR2 mRNA expression levels and uptake of SSTR2-targeting radiotracer [111In]In-DOTATATE. Reversibility of the induced effects was examined after drug-withdrawal. Finally, the effect of VPA on radiosensitivity was investigated. A strong stimulatory effect in BON-1, NCI-H727, and GOT1 cells was observed after HDACi treatment, both on SSTR2 mRNA expression levels and [111In]In-DOTATATE uptake. The effects of the HDACis were largely reversible over a period of seven days, demonstrating largest reductions within the first day. The reversibility profile of the induced effects suggests that proper timing of HDACi treatment is most likely essential for a beneficial outcome. In addition to increasing SSTR2 expression levels, VPA enhanced the radiosensitivity of all cell lines. In conclusion, HDACi treatment increased SSTR2 expression, and radiosensitivity was also enhanced upon VPA treatment.

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Section: Discussionsupporting

confidence: 87%

Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [111In]In-DOTATATE Uptake in NET Cells

Klomp

Dalm

Koetsveld

et al. 2021

Cancers

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“…As MRE11 and NBS1 deficiencies sensitize human cancer cells to etoposide (Hoa et al, 2016), it is worth investigating combination with etoposide and the MRE11 endonuclease inhibitors (PFM 01 and 03) in cancer cell lines as well as tumor xenograft models with different MRE11 expressions. For example, chemo-and radio-resistant small cell lung cancer (SCLC) cells display a higher expression of the MRN complex (Li et al, 2021), targeting MRE11 using PFM 01/03 could potentially improve the response of these cells to etoposide, a key component of the first-line therapy for SCLC treatment.…”

Section: Discussionmentioning

confidence: 99%

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Sun

Soans

Mishina

et al. 2022

Front. Mol. Biosci.

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During a normal topoisomerase II (TOP2) reaction, the enzyme forms a covalent enzyme DNA intermediate consisting of a 5′ phosphotyrosyl linkage between the enzyme and DNA. While the enzyme typically rejoins the transient breakage after strand passage, a variety of conditions including drugs targeting TOP2 can inhibit DNA resealing, leading to enzyme-mediated DNA damage. A critical aspect of the repair of TOP2-mediated damage is the removal of the TOP2 protein covalently bound to DNA. While proteolysis plays a role in repairing this damage, nucleolytic enzymes must remove the phosphotyrosyl-linked peptide bound to DNA. The MRN complex has been shown to participate in the removal of TOP2 protein from DNA following cellular treatment with TOP2 poisons. In this report we used an optimized ICE (In vivo Complex of Enzyme) assay to measure covalent TOP2/DNA complexes. In agreement with previous independent reports, we find that the absence or inhibition of the MRE11 endonuclease results in elevated levels of both TOP2α and TOP2β covalent complexes. We also examined levels of TOP2 covalent complexes in cells treated with the proteasome inhibitor MG132. Although MRE11 inhibition plus MG132 was not synergistic in etoposide-treated cells, ectopic overexpression of MRE11 resulted in removal of TOP2 even in the presence of MG132. We also found that VCP/p97 inhibition led to elevated TOP2 covalent complexes and prevented the removal of TOP2 covalent complexes by MRE11 overexpression. Our results demonstrate the existence of multiple pathways for proteolytic processing of TOP2 prior to nucleolytic processing, and that MRE11 can process TOP2 covalent complexes even when the proteasome is inhibited. The interactions between VCP/p97 and proteolytic processing of TOP2 covalent complexes merit additional investigation.

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“…More importantly, increasing evidence has documented that HDAC inhibitors improve radiosensibility in malignancies, including lung cancer, colon cancer, glioma and squamous cell carcinoma [ 28 – 31 ], suggesting the implication of HDACs in tumor radiation resistance. For instance, HDAC4 and HDAC6 have been indicated to make glioma cells resistant to radiation by maintaining DNA double-strand damage repair and stemness [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma

Yun

Zhang

et al. 2022

J Transl Med

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Background Histone deacetylases (HDACs) have been identified to be implicated in the carcinogenesis and cancer progression. The present study was performed to probe into the effect of HDAC4 on radioresistance of esophageal carcinoma (EC). Methods The expression of HDAC4 in responders and non-responders to radiotherapy was characterized by RT-qPCR, immunohistochemistry, and Western blot analysis. EC cells were exposed to continuous fractionated X-ray irradiation, and their proliferation and apoptosis were evaluated by means of colony formation assay and flow cytometry based Annexin V-FITC/PI apoptosis assay in response to HDAC4 overexpression or silencing. Mechanistic investigation was conducted by means of in silico analysis and dual-luciferase reporter gene assay. Tumor xenografts derived from radioresistant EC cells were exposed to local X-ray irradiation in vivo for validation. Results High expression of HDAC4 was detected in either tumor tissues derived from radiotherapy responders or radioresistant EC cells. Loss of HDAC4 contributed to suppressed proliferation and enhanced apoptosis of radioresistant EC cells. Moreover, our findings revealed that HDAC4 conferred radioresistance of EC by downregulating microRNA-146a (miR-146a). Interleukin-1 receptor-associated kinase 1 (IRAK1) was a target of miR-146a, and its knockdown promoted radiosensitivity. Silencing of HDAC4 radiosensitized EC cells both in vitro and in vivo via the miR-146a/IRAK1 axis. Conclusion Hence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.

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FK228 sensitizes radioresistant small cell lung cancer cells to radiation

Cited by 12 publications

References 31 publications

Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [111In]In-DOTATATE Uptake in NET Cells

Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [111In]In-DOTATATE Uptake in NET Cells

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma

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