MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells

Das, Arabinda; Henderson, Fraser; Alshareef, Mohammed; Porto, Guilherme; Kanginakudru, Indira; Infinger, Libby Kosnik; Vandergrift, William A.; Lindhorst, Scott; Varma, Abhay K.; Patel, Sunil; Cachia, David

doi:10.1007/s12094-020-02456-x

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…High expression levels of MGMT in advanced melanoma patients correlate with resistance to DTIC [ 6 , 7 ] and poor survival [ 8 ]. Likewise, modulation of MGMT expression or activity is expected to be a promising therapeutic target to promote the efficacy of DTIC/TMZ in cancers [ 9 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells

Pei

Zhou

Zeng

et al. 2023

BMC Complement Med Ther

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Background Despite rapid developments in immunotherapy and targeted therapy, dacarbazine (DTIC)-based chemotherapy still has been placed at the first-line for advanced melanoma patients who are after failure of immunotherapy or targeted therapy. However, the limited response rate and survival benefit challenge the DTIC-based chemotherapy for advanced melanoma patients. Methods Two melanoma cell lines, A375 and SK-MEL-28 were cultured with PA and DTIC over a range of concentrations for 72 h and the cell viabilities were detected by CCK8 assay. The Bliss model and ZIP model were used for calculating the synergistic effect of PA and DTIC. DNA double-strand breaks in the two cell lines were examined by the Comet assay, and cell apoptosis was analyzed by flow cytometry. The short hairpin RNA (shRNA)-mediated knockdown, Real-time polymerase chain reaction (RT-PCR) and Western blot were performed for molecular analysis. Results In the present study, we report that Protocatechuic aldehyde (PA) synergistically enhances the cytotoxicity of DTIC to two melanoma cell lines, A375 and SK-MEL-28. The combination of PA and DTIC augments DNA double-strand breaks and increases cell apoptosis. Further mechanism study reveals that PA destabilizes MGMT protein (O-6-Methylguanine-DNA Methyltransferase) through the ubiquitin-proteasome process and directly repairs DTIC-induced genetic lesions. Knockdown of MGMT compromises the synergistic effect between PA and DTIC. Conclusion Our study demonstrates that the bioactive compound, Protocatechuic aldehyde, synergistically promotes the cytotoxicity of DTIC to melanoma cells through destabilization of MGMT protein. It could be a potential candidate for melanoma chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells

Pei

Zhou

Zeng

et al. 2023

BMC Complement Med Ther

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“…These data support the effect of DNA and histone modification in macrophages during LPS activation [ 78 ]. Because of (i) previous reports of DNA methylation ( dnmt ) and histone modification ( ezh ) on sepsis [ 43 , 73 , 79 , 80 ], (ii) possible enhanced cell injury from the presence of O6MeG due to the loss of mgmt for DNA repair [ 72 ], (iii) the availability of the MGMT inhibitor for oncotherapy [ 81 ] and its possible use in some chemotherapeutic strategies as a sepsis immune modulator [ 82 ], and (iv) epigenetic changes in LPS-activated macrophages and the reversal of LPS tolerance by the mgmt inhibitors [ 47 , 83 ], further tests on mgmt will be interesting. Theoretically, MGMT can cause less DNA methylation, leading to better cytokine production, which might correlate with more severe inflammation in single LPS and be beneficial in LPS tolerance.…”

Section: Discussionmentioning

confidence: 99%

Less Severe Lipopolysaccharide-Induced Inflammation in Conditional mgmt-Deleted Mice with LysM-Cre System: The Loss of DNA Repair in Macrophages

Saisorn

Phuengmaung

Issara-Amphorn

et al. 2023

IJMS

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Despite the known influence of DNA methylation from lipopolysaccharide (LPS) activation, data on the O6-methylguanine-DNA methyltransferase (MGMT, a DNA suicide repair enzyme) in macrophages is still lacking. The transcriptomic profiling of epigenetic enzymes from wild-type macrophages after single and double LPS stimulation, representing acute inflammation and LPS tolerance, respectively, was performed. Small interfering RNA (siRNA) silencing of mgmt in the macrophage cell line (RAW264.7) and mgmt null (mgmtflox/flox; LysM-Crecre/−) macrophages demonstrated lower secretion of TNF-α and IL-6 and lower expression of pro-inflammatory genes (iNOS and IL-1β) compared with the control. Macrophage injury after a single LPS dose and LPS tolerance was demonstrated by reduced cell viability and increased oxidative stress (dihydroethidium) compared with the activated macrophages from littermate control mice (mgmtflox/flox; LysM-Cre−/−). Additionally, a single LPS dose and LPS tolerance also caused mitochondrial toxicity, as indicated by reduced maximal respiratory capacity (extracellular flux analysis) in the macrophages of both mgmt null and control mice. However, LPS upregulated mgmt only in LPS-tolerant macrophages but not after the single LPS stimulation. In mice, the mgmt null group demonstrated lower serum TNF-α, IL-6, and IL-10 than control mice after either single or double LPS stimulation. Suppressed cytokine production resulting from an absence of mgmt in macrophages caused less severe LPS-induced inflammation but might worsen LPS tolerance.

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“…Interestingly, DNA methylation impairs DNA transcription and induces programmed cell death, especially apoptosis [ 86 ]. Because (i) previous studies of DNA methylation in sepsis are mentioned [ 41 , 87 , 88 , 89 ], (ii) the possibility that increased O6MeG (due to the loss of mgmt for DNA repair) might enhance cell injury [ 85 ], (iii) the availability of mgmt inhibitor for anti-cancer [ 90 ] that possibly be helpful for sepsis [ 91 ], and (iv) epigenetic changes and in vitro tests of mgmt inhibitors in LPS-activated macrophages [ 45 , 92 ], further tests on mice with the depletion of MGMT enzyme only in the myeloid cells are interesting. Theoretically, MGMT deficiency should interfere with the macrophage activities leading to an anti-inflammatory direction which might be beneficial for treating sepsis hyper-inflammation [ 93 , 94 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Less Severe Polymicrobial Sepsis in Conditional mgmt-Deleted Mice Using LysM-Cre System, Impacts of DNA Methylation and MGMT Inhibitor in Sepsis

Sae-khow

Phuengmaung

Issara-Amphorn

et al. 2023

IJMS

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The O6-methylguanine-DNA methyltransferase (MGMT) is a DNA suicide repair enzyme that might be important during sepsis but has never been explored. Then, the proteomic analysis of lipopolysaccharide (LPS)-stimulated wild-type (WT) macrophages increased proteasome proteins and reduced oxidative phosphorylation proteins compared with control, possibly related to cell injury. With LPS stimulation, mgmt null (mgmtflox/flox; LysM-Crecre/-) macrophages demonstrated less profound inflammation; supernatant cytokines (TNF-α, IL-6, and IL-10) and pro-inflammatory genes (iNOS and IL-1β), with higher DNA break (phosphohistone H2AX) and cell-free DNA, but not malondialdehyde (the oxidative stress), compared with the littermate control (mgmtflox/flox; LysM-Cre-/-). In parallel, mgmt null mice (MGMT loss only in the myeloid cells) demonstrated less severe sepsis in the cecal ligation and puncture (CLP) model (with antibiotics), as indicated by survival and other parameters compared with sepsis in the littermate control. The mgmt null protective effect was lost in CLP mice without antibiotics, highlighting the importance of microbial control during sepsis immune modulation. However, an MGMT inhibitor in CLP with antibiotics in WT mice attenuated serum cytokines but not mortality, requiring further studies. In conclusion, an absence of mgmt in macrophages resulted in less severe CLP sepsis, implying a possible influence of guanine DNA methylation and repair in macrophages during sepsis.

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MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells

Cited by 10 publications

References 24 publications

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells

Less Severe Lipopolysaccharide-Induced Inflammation in Conditional mgmt-Deleted Mice with LysM-Cre System: The Loss of DNA Repair in Macrophages

Less Severe Polymicrobial Sepsis in Conditional mgmt-Deleted Mice Using LysM-Cre System, Impacts of DNA Methylation and MGMT Inhibitor in Sepsis

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