Priming with HDAC Inhibitors Sensitizes Ovarian Cancer Cells to Treatment with Cisplatin and HSP90 Inhibitors

Abstract

Ovarian cancer is the fifth leading cause of cancer deaths. Chemoresistance, particularly against platinum compounds, contributes to a poor prognosis. Histone deacetylase inhibitors (HDACi) and heat shock protein 90 inhibitors (HSP90i) are known to modulate pathways involved in chemoresistance. This study investigated the effects of HDACi (panobinostat, LMK235) and HSP90i (luminespib, HSP990) on the potency of cisplatin in ovarian cancer cell lines (A2780, CaOV3, OVCAR3 and cisplatin-resistant sub-clones). Preincubation with HDACi increased the cytotoxic potency of HSP90i, whereas preincubation with HSP90i had no effect. Preincubation with HSP90i or HDACi 48h prior to cisplatin enhanced the cisplatin potency significantly in all cell lines via apoptosis induction and affected the expression of apoptosis-relevant genes and proteins. For CaOV3CisR and A2780CisR, a preincubation with HDACi for 48–72 h led to complete reversal of cisplatin resistance. Furthermore, permanent presence of HDACi in sub-cytotoxic concentrations prevented the development of cisplatin resistance in A2780. However, triple combinations of HDACi, HSP90i and cisplatin were not superior to dual combinations. Overall, priming with HDACi sensitizes ovarian cancer cells to treatment with HSP90i or cisplatin and has an influence on the development of cisplatin resistance, both of which may contribute to an improved ovarian cancer treatment.

Epithelial–mesenchymal transition and cancer stem cells: A route to acquired cisplatin resistance through epigenetics in HNSCC

“…Considering the importance of biological changes during head and neck cancer treatment, we demonstrated the mecha- and induces apoptosis in cells with the combination of cisplatin (Yousafzai et al, 2019). Although few studies describe the deregulation of HDACs associated with chemoresistance, several works explore the administration of HDAC inhibitors to overcome cisplatin chemoresistance in ovarian cancer, HNSCC, adenoid cystic carcinoma, and lung cancer (Almeida et al, 2017;Iannelli et al, 2020;Rodrigues Moita et al, 2020;Sun et al, 2019). Consequently, targeting HDACs and SIRT1 might be a promising strategy to manage the chemoresistance of HNSCC and perhaps other cancer types.…”

“…Consistent with our findings, it has been demonstrated that increased HDAC1 expression occurs in laryngeal squamous cell carcinoma (LSCC) after treatment with 5‐fluorouracil and cisplatin, and the HDAC1 knockdown significantly restores the sensitivity of LSCC cells (Ding et al, 2021), as well as SIRT1 knockdown in chemoresistant lung cancer cells, substantially reduces cell viability, increases sensitivity, and induces apoptosis in cells with the combination of cisplatin (Yousafzai et al, 2019). Although few studies describe the deregulation of HDACs associated with chemoresistance, several works explore the administration of HDAC inhibitors to overcome cisplatin chemoresistance in ovarian cancer, HNSCC, adenoid cystic carcinoma, and lung cancer (Almeida et al, 2017; Iannelli et al, 2020; Rodrigues Moita et al, 2020; Sun et al, 2019). Consequently, targeting HDACs and SIRT1 might be a promising strategy to manage the chemoresistance of HNSCC and perhaps other cancer types.…”

Mining immune-related LncRNAs in ovarian cancer for prognostic risk modelling and screening of potential target drugs

“…Luminespib is a novel heat shock protein (Hsp90) inhibitor that inhibits the proliferation of various human tumour cell lines and induces Luminespib is a novel Hsp90 inhibitor that inhibits the proliferation of various human tumour cell lines, induces cell cycle arrest and apoptosis, and depletes client proteins in human cancer cells [19] . It is currently commonly used in the treatment of pancreatic cancer and non-small-cell lung cancer [20] .One study experimentally explored the nding that pre-incubation with Panobinostat and Luminespib 48 hours before cisplatin enhanced the potency of cisplatin in all cell lines by inducing apoptosis and affecting the expression of apoptosis-related genes and proteins, sensitising OC cells to Luminespib or cisplatin treatment and affecting the development of cisplatin resistance, or even completely reversing Cisplatin resistance, which may help to improve OC treatment [21] .Combination with our studies, Luminespib may play an important role in the treatment of drug-resistant OC.…”

Histone Modifying Enzymes in Gynaecological Cancers

“…This potential synergistic effect of HDACis warrants further investigation to determine if HR proficient tumours can be sensitised to PARP inhibition. Interestingly, Panobinostat may also be able to impart re-sensitisation of platinum-based compounds as demonstrated in cisplatin resistant ovarian cancer cell lines [ 113 ], possibly by rewiring these cells to a BRCA-deficiency like phenotype.…”