MIM1, the Mcl-1 - specific BH3 mimetic induces apoptosis in human U87MG glioblastoma cells

Toxicol In Vitro. 2018 Dec;53:126-135. doi: 10.1016/j.tiv.2018.08.007. Epub 2018 Aug 19.

Abstract

Glioblastoma multiforme (GBM) is the most common and high aggressive malignant brain tumor. Despite evolving oncology treatment and novel chemotherapeutic agents the median survival of patients diagnosed with GBM is only 12-15 months. This grim fact highlights necessity to identify new drugs that could improve the effectiveness of GBM patients treatment. MIM1 is a specific low molecular Mcl-1 protein inhibitor able to induce Mcl-1-dependent cancer cells death. The aim of this study was to examine the effect of MIM1 as well as MIM1 and temozolomide (TMZ) mixture on cell viability, apoptosis and cell cycle progression in human U87MG glioblastoma cells. Cell viability was performed by the WST-1 assay. Mitochondrial membrane potential, Annexin V assay, DNA fragmentation and cell cycle distribution were determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results show that MIM1 and MIM1/TMZ mixture decrease glioblastoma cells viability in a dose- and time- dependent manner. Moreover, the exposure of U87MG cells to MIM1 and MIM1/TMZ mixture causes mitochondrial dysfunction as well as DNA fragmentation and cell cycle arrest at G2/M phase. This study provides for the first time convincing evidence that BH3 mimetic MIM1, which inhibits Mcl-1 antiapoptotic protein may be an efficacious molecule able to induction of apoptosis and sensitize GBM cells to alkylating agents.

Keywords: Apoptosis; BH3 mimetic; Glioblastoma; MIM1; Mcl-1 protein; Temozolomid.

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology*
  • Apoptosis / drug effects
  • Brain Neoplasms / drug therapy
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dose-Response Relationship, Drug
  • Glioblastoma / drug therapy
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Temozolomide
  • Thiazoles / pharmacology*

Substances

  • Antineoplastic Agents, Alkylating
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Thiazoles
  • Dacarbazine
  • Temozolomide