Abstract
Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma in childhood with a poor prognosis, highlighting the need for new treatment strategies. Here we identify a synergistic interaction of the second-generation histone deacetylase inhibitor (HDACI) JNJ-26481585 and common chemotherapeutic drugs (i.e. Doxorubicin, Etoposide, Vincristine, Cyclophosphamide and Actinomycin D) to trigger apoptosis in RMS cells. Importantly, JNJ-26481585/Doxorubicin cotreatment also significantly suppresses long-term clonogenic survival of RMS cells and tumor growth in vivo in a preclinical RMS model. Mechanistically, JNJ-26481585/Doxorubicin cotreatment causes upregulation of the BH3-only proteins Bim and Noxa as well as downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL. These changes in the ratio of pro- and antiapoptotic Bcl-2 proteins contribute to JNJ-26481585/Doxorubicin-mediated apoptosis, since knockdown of Bim or Noxa significantly inhibits cell death. Also, JNJ-26481585 and Doxorubicin cooperate to stimulate activation of Bax and Bak, which is required for JNJ-26481585/Doxorubicin-induced apoptosis, since silencing of Bax or Bak protects against apoptosis. Consistently, overexpression of Bcl-2 significantly reduces JNJ-26481585/Doxorubicin-mediated apoptosis. JNJ-26481585/Doxorubicin cotreatment leads to caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescues cells from apoptosis. In conclusion, the second-generation HDACI JNJ-26481585 cooperates with chemotherapeutics to engage mitochondrial apoptosis in RMS cells, demonstrating that JNJ-26481585 represents a promising strategy for chemosensitization of RMS.
Highlights
RMS is one of the most common soft-tissue sarcomas in children, which comprises two major subtypes, i.e. alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) [1, 2]
Suboptimal concentrations of JNJ-26481585 synergized with various anticancer drugs, including the topoisomerase II inhibitors Doxorubicin and Etoposide, the vinca alkaloid Vincristine, the alkylating agent Cyclophosphamide and the cytotoxic antibiotic Actinomycin D, to trigger apoptosis in RMS cells as confirmed by calculation of (CI), while treatment with JNJ-26481585 alone induced apoptosis in a dosedependent manner
histone deacetylase inhibitor (HDACI) as a class turned out to be active against RMS cells in a recent screen of a custom library of about 200 compounds including chemotherapeutics, Food and Drug Administration-approved drugs and small molecules with biological activity [22]
Summary
RMS is one of the most common soft-tissue sarcomas in children, which comprises two major subtypes, i.e. alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) [1, 2]. Despite multimodal treatment regimens and advances in combination chemotherapy, patients with primary metastatic disease or relapse are largely resistant to current treatment protocols and have a dismal chance for cure of less than 20% [3]. This highlights the high medical need to develop new treatment regimens in RMS to improve the poor prognosis of these patients. Since HDACs have been shown to be upregulated in many cancer entities, they are considered to represent potential targets for treatment strategies [5, 6]. As a relatively new class of anticancer agents, HDACIs have been shown to induce apoptosis in a variety of cancer cells [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
