Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling

Toxicol In Vitro. 2018 Oct;52:306-313. doi: 10.1016/j.tiv.2018.07.001. Epub 2018 Jul 9.

Abstract

Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis-chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT-PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of <1. Combination of TMZ and VP increased the ratio of Bax to Bcl-2 expression and thus shifted the equilibrium of cells towards apoptosis. Our findings suggest that the synergistic growth inhibition that was observed in combination treatment group may in part relate to increase in apoptosis. The combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.

Keywords: Apoptosis; Glioblastoma; Temozolmide; Verapamil.

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology*
  • Apoptosis / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Drug Synergism
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Temozolomide
  • Verapamil / pharmacology*

Substances

  • Antineoplastic Agents, Alkylating
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Dacarbazine
  • Verapamil
  • Temozolomide