Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models

Cancer Lett. 2018 Mar 1;416:138-148. doi: 10.1016/j.canlet.2017.11.041. Epub 2017 Dec 13.

Abstract

Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor with a median patient survival of less than two years, even with the optimal standard of care, namely, surgical resection followed by radiotherapy with adjuvant temozolomide chemotherapy. Long-term survival is extremely rare and there is a tremendous need for novel GBM therapies. Following our prior reports on the anticancer activity of osmium(VI) nitrido compounds and their effectiveness against cancer initiating cells, we investigated the efficacy of Os(VI) on GBM initiating cells in vitro and in vivo. Conventional MTT and 3D cytotoxicity assays revealed that patient-derived GBM models were sensitive to cisplatin, TMZ, and two Os(IV) derivatives. Rapid cell death occurred at low micromolar concentrations of the Os(IV) compounds. Cell cycle analysis, Os uptake studies, and cellular distribution experiments provided further insight into the anticancer properties of these compounds, indicating differential uptake for both compounds and a modest G2/M arrest after treatment. Moreover, in vivo experiments showed a significant increase in survival after a single intracranial chemotherapeutic injection, results that warrant further studies using this approach.

Keywords: Glioblastoma; In vivo efficacy; Osmium(VI); Patient-derived models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Coordination Complexes / pharmacology*
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • HeLa Cells
  • Humans
  • Kaplan-Meier Estimate
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Osmium / pharmacology*
  • Temozolomide
  • Xenograft Model Antitumor Assays*

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Osmium
  • Dacarbazine
  • Cisplatin
  • Temozolomide