Abstract
Abstract The mammalian target of rapamycin (mTOR) pathway is one of the most important oncogenic pathways in cancer, and the upregulation of the mTOR pathway is frequently observed in human osteosarcoma (OS). In this study, we demonstrated for the first time that cucurbitacin B, a plant-derived tetracyclic triterpenoid, is a direct mTOR inhibitor in OS using drug affinity responsive target stability (DARTS) analysis. Binding of cucurbitacin B to mTOR resulted in the inhibition of mTOR phosphorylation in MG-63 and SAOS-2 human OS cells in vitro, which was further confirmed by the inhibition of ribosomal S6 protein kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). This finding led us to hypothesize the possible use of cucurbitacin B as a single agent as well as in combination with methotrexate (MTX) for OS treatment. Cucurbitacin B in combination with MTX synergistically inhibited OS cell growth in vitro such that combination index (CI) < 0.9. Murine xenografts treated with either low-dose cucurbitacin B (LD-CuB, 0.5 mg/kg body weight) or low-dose MTX (LD-MTX, 150 mg/kg) alone failed to decrease tumor size. However, combined therapy at identical concentrations inhibited tumor growth by 62% vs LD-CuB and 81% vs LD-MTX (p<0.001). The effect persisted even at a two-thirds decrease (50 mg/kg) in the MTX dose. In conclusion, cucurbitacin B is a direct inhibitor of mTOR, and the combined use of cucurbitacin B with MTX showed promising antiproliferative activity against human OS. The use of this combination should be explored further in clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2011-3546
Published Version
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.
