A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
Open accessAbstract
Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death. Senescence occurred following cisplatin- or Taxol-treatment in cell lines from both cancer types and was associated with decreased histone 3 (H3) acetylation and increased Bcl-xL expression: the latter a biomarker of senescence and target of anti-senescence therapeutics, or senolytics. Since H3 acetylation and Bcl-xL expression were altered in senescence, we subsequently evaluated pano as a senolytic in chemotherapy-treated cancer cells enriched for senescent cells. Pano caused cell death at significantly higher rates compared to repeat dosing with chemotherapy. This was associated with decreased expression of Bcl-xL and increased acetylated H3, reversing the expression patterns observed in senescence. These data support evaluating pano as a post-chemotherapy senolytic with the potential to kill persistent senescent cells that accumulate during standard chemotherapy in NSCLC and HNSCC.
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HDAC inhibitor treatment induces chromatin relaxation, boosts DNA damage response signalling and causes apoptosis; this is probably the first reported successful senolytic approach, later supported by panobinostat's senolytic activity.
“treatment with histone deacetylase (HDAC) inhibitors, which induce chromatin relaxation, boosts DDR signalling with consequent cell death by apoptosis. This treatment is probably the first reported example of a successful senolytic approach52, which was later supported by the reported senolytic activity of the HDAC inhibitor panobinostat55”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [55]
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- Authors
- Samaraweera, L., Adomako, A., Rodriguez-Gabin, A., & McDaid, H. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- McDaid, Hayley M.
- ORCID
- McDaid, Hayley M.
- Venue
- Scientific Reports
- Published
- 2017-05-15
- Volume
- 7
- Issue
- 1
- Pages
- 1900-1900
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5432488
- OpenAlex
- W2612435930
- Cited by
- 183
- References
- 44
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 17 · 2023: 21 · 2022: 28 · 2021: 26 · 2020: 26 · 2019: 16 · 2018: 11 · 2017: 2
- FWCI
- 11.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Breast Cancer Research Foundation
- Albert Einstein Cancer Center (P30CA013330)
- National Institutes of Health (5k12ca132783-12)
- National Cancer Institute (K12-CA132783, R01CA077263, CA 077263, CA132783, P30CA013330)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- panobinostat, senolytics, histone deacetylase inhibitors, non-small cell lung cancer, head and neck squamous cell carcinoma, paclitaxel, cisplatin, cellular senescence, Bcl-xL, histone H3 acetylation, drug synergy
- MeSH terms
- Squamous Cell Carcinoma of Head and Neck, Panobinostat, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Survival, Dose-Response Relationship, Drug, Drug Synergism, Humans, Lung Neoplasms, Cellular Senescence, Apoptosis, Paclitaxel, Cell Line, Tumor, Histone Deacetylase Inhibitors
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