Suberanilohydroxamic acid (vorinostat) synergistically enhances the cytotoxicity of doxorubicin and cisplatin in osteosarcoma cell lines

Abstract

Osteosarcoma is the most common primary bone cancer in children and is a highly malignant disease, in which 25% of patients present with metastasis at diagnosis. Considerable advances in the treatment of localized disease have been achieved since the introduction of combined modality treatment, increasing the prognosis of overall survival to 70%. Yet, established therapies have only limited success in treating both metastatic disease and nonresponders to primary chemotherapy. Therefore, new therapeutic approaches are required, particularly for the control of osteosarcoma in these patient groups. Epigenetically modifying substances are a class of emerging drugs that have shown therapeutic potential in various hematological and solid cancers. We examined the cytotoxic effects of 5-azacitidine, 3-deazaneplanocin A, and suberanilohydroxamic acid (SAHA) on osteosarcoma cell lines HOS, MG-63, MNNG, and ZK-58. SAHA was the only chemical agent that exerted a strong, growth-limiting effect in all cell lines tested. The growth-limiting effect of SAHA was accompanied by features characteristic of apoptotic death. We found that cotreatment with SAHA and cisplatin showed strong synergism in all cell lines. The effect of cotreatment with SAHA and doxorubicin was cell line dependent. In the cell lines HOS, MG-63, and MNNG, the combined effect was synergistic, whereas in the cell line ZK-58, SAHA antagonized doxorubicin. The strong synergism of SAHA indicated that in combination with cisplatin, it might enable a promising add-on to current therapy regimens. However, considering the cell line-dependent effect that was found when SAHA was combined with doxorubicin, further experimentation is needed.

Vorinostat: a histone deacetylases (HDAC) inhibitor ameliorates traumatic brain injury by inducing iNOS/Nrf2/ARE pathway

“…Vorinostat is a histone deacetylases (HDAC) inhibitor and chemically a suberanilohydroxamic acid [12]. HDAC inhibitors are reported for their anti-depressant, anti-epileptic properties and are recommended for neurodegenerative diseases [1].…”

Molecular characterization of immunogenic cell death indicates prognosis and tumor microenvironment infiltration in osteosarcoma

“…In contrast, the low ICD-risk patients displayed better responses to DMOG, Midostaurin, and Shikonin. Pettke A et al reported that vorinostatin synergistically enhanced the cytotoxicity of doxorubicin and cisplatin in OS, which may be a promising addition to present treatment regimens (48). Midostaurin (PKC412), a derivative of staurosporine, has been proven to induce the apoptosis of Ewing's sarcoma cell lines and significantly suppress xenograft tumor growth (49).…”

Osteosarcoma mechanobiology and therapeutic targets

“…A DNA methyltransferase inhibitor, decitabine, improved the chemosensitivity of OS cells to cisplatin when used together (Chaiyawat et al, 2020), as well as providing an opportunity to promote OS differentiation through expression of the oestrogen receptor ER-α (Osuna et al, 2019). Histone deacetylase inhibitors such as panobinostat, domatinostat, entinostat, vorinostat, trichostatin A and sodium butyrate have been tested alone (Deng et al, 2016;McGuire et al, 2020;Mu et al, 2015;Rao-Bindal et al, 2013;Torres et al, 2020;Xie et al, 2016) or in combination with doxorubicin/cisplatin (Pettke et al, 2016) or decitabine (Capobianco et al, 2014) and have shown anti-proliferative and antimetastatic effect in OS cells. increase in Young's modulus that is accompanied with increased traction forces and spreading area (Lo et al, 2000).…”