Synergistic Interaction of the Class IIa HDAC Inhibitor CHDI0039 with Bortezomib in Head and Neck Cancer Cells.
Christian SchrenkLukas M BollmannCorinna HaistArthur BisterConstanze WiekMaria WeckerDennis RothPatrick PetzschKarl KöhrerAlexandra HamacherHelmut HanenbergGeorg FluegenMatthias Ulrich KassackPublished in: International journal of molecular sciences (2023)
In contrast to class I/IIb/pan histone deacetylase inhibitors (HDACi), the role of class IIa HDACi as anti-cancer chemosensitizing agents is less well understood. Here, we studied the effects of HDAC4 in particular and the class IIa HDACi CHDI0039 on proliferation and chemosensitivity in Cal27 and cisplatin-resistant Cal27CisR head and neck squamous cell cancer (HNSCC). HDAC4 and HDAC5 overexpression clones were generated. HDAC4 overexpression (Cal27_HDAC4) increased proliferation significantly compared to vector control cells (Cal27_VC). Chicken chorioallantoic membrane (CAM) studies confirmed the in vitro results: Cal27_HDAC4 tumors were slightly larger than tumors from Cal27_VC, and treatment with CHDI0039 resulted in a significant decrease in tumor size and weight of Cal27_HDAC4 but not Cal27_VC. Unlike class I/pan-HDACi, treatment with CHDI0039 had only a marginal impact on cisplatin cytotoxicity irrespective of HDAC4 and HDAC5 expression. In contrast, the combination of CHDI0039 with bortezomib was synergistic (Chou-Talalay) in MTT and caspase 3/7 activation experiments. RNAseq indicated that treatment with CHDI0039 alters the expression of genes whose up- or downregulation is associated with increased survival in HNSCC patients according to Kaplan-Meier data. We conclude that the combination of class IIa HDACi with proteasome inhibitors constitutes an effective treatment option for HNSCC, particularly for platinum-resistant cancers.
Keyphrases
- histone deacetylase
- signaling pathway
- newly diagnosed
- squamous cell
- magnetic resonance
- end stage renal disease
- cell proliferation
- induced apoptosis
- magnetic resonance imaging
- cell death
- genome wide
- young adults
- deep learning
- chronic kidney disease
- contrast enhanced
- oxidative stress
- papillary thyroid
- ejection fraction
- computed tomography
- electronic health record
- long non coding rna
- big data
- pi k akt
- machine learning
- weight gain