Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

Oncol Rep. 2019 Mar;41(3):1883-1892. doi: 10.3892/or.2019.6970. Epub 2019 Jan 16.

Abstract

Temozolomide (TMZ) is a widely used chemotherapeutic agent for glioblastoma multiforme (GBM). However, chemoresistance to TMZ is still a major obstacle for GBM patients. An abundance of candidates has been reported to improve the chemotherapeutic sensitization of TMZ. In the present study, it was demonstrated that momelotinib (MTB) enhanced the sensitivity of glioma cells to TMZ in vitro, as evidenced by a noticeable decrease in cell growth and a significant increase in apoptosis and autophagy following treatment with the combination of TMZ and MTB compared to TMZ alone. Mechanistically, MTB and TMZ combination treatment reduced U251 cell growth by activating both apoptosis and autophagy pathways. MTB potentiated TMZ to inhibit the phosphorylation of JAK2 and STAT3 in U251 cells, resulting in the inactivation of JAK2/STAT3 signaling pathways. Moreover, we investigated the effect of MTB in xenograft tumor model mice. MTB and TMZ combination reduced tumor weight, decreased the expression of Ki‑67, P62, p‑STAT3 and p‑JAK2, while increased the ratio of LC3‑II/I and the expression of caspase‑3 and Beclin1 in vivo. Importantly, this combination was well tolerated, and caused significant tumor growth inhibition in the GBM xenografts. In summary, the present study provides pharmacological evidence that MTB has potential value in the treatment of GBM.

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Autophagy / drug effects
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Janus Kinase 2 / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Temozolomide / pharmacology*
  • Temozolomide / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • JAK2 protein, human
  • Janus Kinase 2
  • Temozolomide