Studies examining the synergy between Dihydrotanshinone and Temozolomide against MGMT+ glioblastoma cells in vitro: Predicting interactions with the blood-brain barrier

Biomed Pharmacother. 2019 Jan;109:386-390. doi: 10.1016/j.biopha.2018.10.069. Epub 2018 Nov 3.

Abstract

We showed previously that Dihydrotanshinone (DHT) augments temozolomide (TMZ) efficacy by inducing reactive oxygen species production in an in vitro model. Here, the underlying basis of the synergistic effect and the ability of DHT to potentially pass the blood brain barrier (BBB) is investigated using an in vitro model. Trypan blue exclusion assays were used to determine effects of DHT/TMZ combinatorial treatment on GBM cell viability. ELISA was utilized to determine effects on NFkB levels after singular and combinatorial treatment. An in vitro model of the BBB was constructed to predict the potential of DHT to penetrate the BBB in vivo. DHT and TMZ synergistically reduce cancer cell viability, NFkB activity, and markedly halt cell cycle progression. This regimen was also shown to exert minimal effects on astrocytes. Finally, DHT was shown to have the potential of passing through the BBB to a similar extent as TMZ and that paclitaxel's oncolytic effects are completely ablated in the presence of our in vitro BBB. Our data confirms the synergistic interaction between DHT and TMZ and also highlights the potential of combination treatment to sequester NFkB activity and inhibit cell cycle progression. The encouraging data with the BBB model show that the DHT/TMZ combination may be clinically useful and warrants future in vivo testing.

Keywords: Blood-brain barrier; Dihydrotanshinone; Glioblastoma; NFkB; Synergy; Temozolomide.

MeSH terms

  • Abietanes / administration & dosage
  • Abietanes / chemistry
  • Abietanes / metabolism*
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Coculture Techniques
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Drug Synergism
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Predictive Value of Tests
  • Temozolomide / administration & dosage
  • Temozolomide / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Abietanes
  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Proteins
  • tanshinone
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide