The antiproliferative effect of spectinabilins from Streptomyces spectabilis on hepatocellular carcinoma cells in vitro and in vivo

Bioorg Chem. 2019 Dec:93:103311. doi: 10.1016/j.bioorg.2019.103311. Epub 2019 Sep 24.

Abstract

Spectinabilin (1), spectinabilin derivative (2), and a new analogue, 2-demethyl-spectinabilin (3) were isolated from the fermentation broth of a soil-borne Streptomyces spectabilis strain. The structure of the new compound was elucidated by a detailed spectroscopic data analysis including data from CD spectra. Spectinabilin (1) demonstrated cytotoxicity against five human cancer cell lines, with IC50 values ranging from 18.7 ± 3.1 to 34.6 ± 4.7 μM, while derivatives 2 and 3 showed weak cytotoxicities. Notably, 1 inhibited the growth and proliferation of the hepatocellular carcinoma cell lines SMMC7721 and HepG2 in a time- and dose-dependent manner. Further study demonstrated that 1 caused G2/M phase cell cycle arrest in SMMC7721 and HepG2 cells through decreasing the protein levels of cyclin B1 and cdc2 as well as increasing that of p21. Compound 1 downregulated the protein expression of Bcl-2, upregulated Bax, and activated the cleavage of caspase-9 and -3 as a result of inducing apoptosis in SMMC7721 and HepG2 cells. Furthermore, the antitumor effect of 1 in SMMC7721 and HepG2 cells was mediated by the PI3K/AKT signaling pathway. In addition, 1 also suppressed tumor growth in vivo though inducing cell cycle arrest and apoptosis.

Keywords: 2-Demethyl-spectinabilin; HepG2; Hepatocellular carcinoma; SMMC7721; Spectinabilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrones / chemistry*
  • Pyrones / isolation & purification
  • Pyrones / pharmacology
  • Pyrones / therapeutic use
  • Signal Transduction / drug effects
  • Streptomyces / chemistry*
  • Streptomyces / metabolism
  • Up-Regulation / drug effects
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrones
  • bcl-2-Associated X Protein
  • spectinabilin
  • Proto-Oncogene Proteins c-akt

Supplementary concepts

  • Streptomyces spectabilis