Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin

Ahmadinejad, Fereshteh; Bos, Tasia; Hu, Bin; Britt, Erin; Koblinski, Jennifer E.; Souers, Andrew J.; Leverson, Joel D.; Faber, Anthony C.; Gewirtz, David A.; Harada, Hisashi

doi:10.1124/molpharm.121.000354

Cited by 19 publications

(16 citation statements)

References 88 publications

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“…We and others have demonstrated that the senolytic ABT-263 (navitoclax), is effective at the elimination of tumor cells induced into senescence by various chemotherapeutic strategies in breast, lung, head and neck and prostate tumor cells ( 14 – 16 ). However, one fundamental limitation in the use of ABT-263 is thrombocytopenia, given that the target of ABT-263 is the Bcl-xL protein, upon which platelets depend for survival ( 50 ).…”

Section: Resultsmentioning

confidence: 99%

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

et al. 2023

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Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.

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Section: Resultsmentioning

confidence: 99%

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

et al. 2023

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“…Andrew Yeudall (Augusta University, GA). Cells were cultured in DMEM (Thermo Fisher Scientific, MA) supplemented with 10% (v/v) fetal bovine serum (GeminiBio, CA), 100 U/ml penicillin G sodium and 100 µg/ml streptomycin sulfate (Thermo Fisher Scientific, MA) at the 37°C incubator with 5% CO 2 (Ahmadinejad et al, 2022).…”

Section: Cell Culture and Drug Treatmentmentioning

confidence: 99%

“…Clonogenic survival assay was performed as previously described (Ahmadinejad et al, 2022;Xie et al, 2022). Cells were seeded at a low density (1 x 10 2 HN12 in 6-well plates or 5 x 10 2 HN30 in 10 cm dishes), and exposed to 5 µM cisplatin in the absence and presence of 1 µM PF-04457845.…”

Section: Toxicity Of Cisplatin and Faah Inhibition On Cancer Cells By...mentioning

confidence: 99%

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Chen¹,

Wang²,

Raymond³

et al. 2023

Mol Pharmacol

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Cisplatin is a potent first-line therapy for many solid malignancies such as breast, ovarian, lung, testicular and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits antiinflammatory effects; however, little is known about its role in cisplatin nephrotoxicity.The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatininduced AKI. Male wild-type C57BL6 (WT) and Faah −/− mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later.Faah −/− mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (PEA and OEA), attenuated NF-κB/p65 activity, DNA damage markers p53, p21 and decreased expression of the inflammatory cytokine IL-1β as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity.

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“…For example, H1299 non-small cell lung cancer cells exposed to camptothecin can regain proliferative ability upon discontinuation of drug exposure, although recovery from the senescent growth arrest was a rare event (approximately, 1 in 10 6 cells) [ 69 ]. Our own laboratory has also previously demonstrated that several tumor cell types (specifically, H460 lung, HCT116 colon, HN30 head and neck, Myc-CaP prostate, and 4T1 breast cancer cells) induced into senescence by exposure to chemotherapy or ionizing radiation can overcome the senescent growth arrest following short-term drug or radiation treatment [ 70 , 71 , 72 ].…”

Section: Oncogene-induced Senescencementioning

confidence: 99%

Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells

Saleh

Khasawneh

Himsawi

et al. 2022

IJMS

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Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence. Oncogenic processes that induce senescence include overexpression/hyperactivation of H-Ras, B-Raf, and cyclin E as well as inactivation of PTEN. Oncogenic viruses, such as Human Papilloma Virus (HPV), have also been shown to induce senescence. High-risk strains of HPV drive the immortalization, and hence transformation, of cervical epithelial cells via several mechanisms, but primarily via deregulation of the cell cycle, and possibly, by facilitating escape from senescence. Despite the wide and successful utilization of HPV vaccines in reducing the incidence of cervical cancer, this measure is not effective in preventing cancer development in individuals already positive for HPV. Accordingly, in this commentary, we focus on the potential contribution of oncogene and HPV-induced senescence (OIS) in cervical cancer. We further consider the potential utility of senolytic agents for the elimination of HPV-harboring senescent cells as a strategy for reducing HPV-driven transformation and the risk of cervical cancer development.

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Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin

Cited by 19 publications

References 88 publications

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells

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