Palbociclib induces DNA damage and inhibits DNA repair to induce cellular senescence and apoptosis in oral squamous cell carcinoma

Wang, Tong Hong; Leu, Yann‐Lii; Lee, Yun‐Shien; Lian, Jang-Hau; Hsieh, Hsi‐Lung; Chen, Chi-Yuan

doi:10.1016/j.jfma.2020.12.009

Cited by 26 publications

(17 citation statements)

References 44 publications

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“…In addition, proteins such as cell cycle checkpoint kinases Chk2 and p53 are also activated [59] . p53 protein can promote the transcription and expression of the cyclin‐dependent kinase inhibitor p21, which exerts a crucial role in regulating the cell cycle [60,61] . Therefore, the protein expression of p‐ATM, ATM, γH2AX, H2AX, Chk2, p53 and p21, was detected in this study.…”

Section: Resultsmentioning

confidence: 57%

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Liú

Cheng

Tang

et al. 2022

Chemistry & Biodiversity

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Methylglyoxal (MGO) is a reactive carbonyl species that can cause cellular damage and is closely related to kidney disease, especially diabetic nephropathy. The toxic effect of MGO (0.5, 1, and 2 mM) on human embryonic kidney (HEK293) cells and its underlying mechanisms were explored in this study. Cell viability, apoptosis and the signaling pathways were measured with MTT, fluorescent staining and western blot experiments, the results showed that MGO could induce oxidative stress and cell inflammation, the level of reactive oxygen species (ROS) increased, and p38MAPK, JNK and NF‐κB signaling pathways were activated. Meanwhile, MGO also induced DNA damage. The expression of DNA oxidative damage marker 8‐hydroxy‐2’‐deoxyguanosine (8‐OHdG) increased, the expression of double‐strand break marker γH2AX increased significantly, and ATM/Chk2/p53 DNA damage response signaling pathway was activated. Furthermore, the expression of the receptor for advanced glycation end products (RAGE) also increased. Finally, mitochondrial membrane potential (MMP) decreased, fluorescence intensity of Hoechst33258 increased, and the protein expression ratio of Bax/Bcl‐2 increased significantly after the treatment of MGO. These results demonstrated that MGO might induce HEK293 cells damage by regulating oxidative stress, inflammation, DNA damage, and cell apoptosis, which revealed the specific mechanisms of MGO‐induced damage to HEK293 cells.

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Section: Resultsmentioning

confidence: 57%

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Liú

Cheng

Tang

et al. 2022

Chemistry & Biodiversity

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“…Although ABT-263 has been described as a broad-spectrum senolytic and eliminated various senescent cells in vivo (Bussian et al, 2018;Chang et al, 2016;Childs et al, 2016;Demaria et al, 2017;Kim et al, 2017;Pan et al, 2017), a cell-type specificity has been reported before in senescent preadipocytes (Zhu et al, 2016) and doxorubicininduced senescent breast cancer cells (Shahbandi et al, 2020). Since a (transient) DDR can be activated by the drugs we used to induce senescence (Montecucco et al, 2015;Niu et al, 2015;Tacar et al, 2013;Wang et al, 2020), and since the senescence transcriptome was similar between senescent cells triggered via different drugs, it might be possible that senescence is triggered via DDR and that a similar senescence phenotype is elicited in a given cell line, regardless of the DDR inducer.…”

Section: Discussionmentioning

confidence: 95%

The Cancer SENESCopedia: A delineation of cancer cell senescence

Jochems¹,

Thijssen²,

Conti³

et al. 2021

Cell Reports

122

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“…Regarding the results of our colony-forming assays, clear evidence is found for the higher effect of palbociclib on clonogenicity, survival, and senescence, since palbociclib blocks the cell cycle, but does not lead to cell death ( 28 ). Senescence can be triggered by, e.g., cellular stress like DNA damage or aging processes and could lead to irreversible growth arrest called stress-induced or replicative senescence, respectively ( 29 ).…”

Section: Discussionmentioning

confidence: 82%

Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation

et al. 2021

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IntroductionSeveral kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer.MethodIn our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms.ResultsThe CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib.ConclusionThe effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.

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Palbociclib induces DNA damage and inhibits DNA repair to induce cellular senescence and apoptosis in oral squamous cell carcinoma

Cited by 26 publications

References 44 publications

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

The Cancer SENESCopedia: A delineation of cancer cell senescence

Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation

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