An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent

  • Authors:
    • Su Jung Hwang
    • Hyeung-Geun Park
    • Yohan Park
    • Hyo-Jong Lee
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  • Published online on: October 11, 2016     https://doi.org/10.3892/ijo.2016.3726
  • Pages: 2480-2486
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Abstract

Previously, we reported that α-quaternary chiral lactam derivatives have broad spectrum anticancer activity. However, the underlying molecular mechanisms and its relevance are largely unknown. In the present study, we report progress on α-quaternary chiral lactam analogues that address this, focusing on the novel analogue YH-304 as a candidate to broadly target human cancer cells. The effect of YH-304 on cell transformation was assessed by clonogenic assay in non-small cell lung cancer cells (NSCLCs) A549 and 226B. Proapoptotic activity of YH-304 was determined by TUNEL assay and cleaved PARP, cleaved caspase-9, and Bax as markers for apoptosis. The p53-dependency and therapeutic spectrum of YH-304 was assessed by western blot analysis, real-time PCR, and cell viability assays in cells expressing endogenous wild or mutant p53. The effect of YH-304 on angiogenesis in vivo was examined by bFGF-mediated angiogenesis assay in zebrafish. Finally, the effect of YH-304 on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of YH-304 on bFGF-mediated angiogenesis was assessed using western blotting. We found that YH-304 significantly decreases the colony-forming activities of both A549 and 226B cells, inducing cellular apoptosis. Unlike nutlin-3 (p53 pathway activator), YH-304 did not affect the expression levels of p53 and its target gene such as p21 and thus showed p53-independent anticancer activity with broad spectrum. In addition, YH-304 inhibited bFGF-induced angiogenesis in vivo through mediating AKT and ERK signaling pathway, which plays an important role in bFGF activation and angiogenesis. Taken together, our data indicate that YH-304 may represent a novel therapeutic option for the treatment of cancer in a p53-independent manner.
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December-2016
Volume 49 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Hwang SJ, Park H, Park Y and Lee H: An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent. Int J Oncol 49: 2480-2486, 2016
APA
Hwang, S.J., Park, H., Park, Y., & Lee, H. (2016). An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent. International Journal of Oncology, 49, 2480-2486. https://doi.org/10.3892/ijo.2016.3726
MLA
Hwang, S. J., Park, H., Park, Y., Lee, H."An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent". International Journal of Oncology 49.6 (2016): 2480-2486.
Chicago
Hwang, S. J., Park, H., Park, Y., Lee, H."An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent". International Journal of Oncology 49, no. 6 (2016): 2480-2486. https://doi.org/10.3892/ijo.2016.3726