Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice

Siddhartha Kumar Mishra, Ju Hee Kang, Chang Woo Lee, Seung Hyun Oh, Jun Sun Ryu, Yun Soo Bae, Hwan Mook Kim

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosisinducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties.

Original languageEnglish
Pages (from-to)219-226
Number of pages8
JournalMolecules and Cells
Volume36
Issue number3
DOIs
StatePublished - Sep 2013

Keywords

  • Anesthesia
  • Anticancer
  • Apoptosis induction
  • Midazolam
  • ROS scavenging

Fingerprint

Dive into the research topics of 'Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice'. Together they form a unique fingerprint.

Cite this