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γ-Tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways

Chandan Wilankar1, Nazir M Khan, Rahul Checker

  • 1Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Current Pharmaceutical Design
|July 22, 2011
PubMed

Insights

Gamma-tocotrienol (GT) inhibits human T cell lymphoma Jurkat cell proliferation and induces apoptosis by increasing mitochondrial ROS and activating intrinsic and extrinsic pathways. GT shows differential cytotoxicity, sparing normal cells.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Tocotrienols, members of the vitamin E family, exhibit antioxidant, anti-inflammatory, and antitumor properties.
  • Understanding the specific mechanisms of tocotrienols against cancer is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the anti-proliferative and apoptotic effects of alpha-tocotrienol (AT) and gamma-tocotrienol (GT) on human T cell lymphoma Jurkat cells.
  • To elucidate the molecular pathways involved in the antitumor effects of GT.

Main Methods:

  • Jurkat cells were treated with AT and GT to assess proliferation and apoptosis.
  • Mitochondrial ROS, MAPK signaling (JNK, ERK, p38), calcium levels, mitochondrial membrane potential, and cytochrome c release were analyzed.
  • Gene expression of Bax and Bcl-xl, surface expression of Fas and FasL, caspase activation, and PARP degradation were evaluated.
  • Cytotoxicity was assessed in normal human peripheral blood mononuclear cells.
  • Cellular uptake of AT and GT was quantified.

Main Results:

  • GT, but not AT, inhibited Jurkat cell proliferation and induced apoptosis in a dose-dependent manner.
  • GT treatment elevated mitochondrial ROS, activated JNK, suppressed ERK and p38 MAPK, induced calcium release, mitochondrial membrane depolarization, and cytochrome c release.
  • GT increased Bax expression, decreased Bcl-xl expression, upregulated Fas and FasL, activated caspases, and degraded PARP.
  • GT demonstrated differential cytotoxicity, being toxic to lymphoma cells but not normal lymphocytes.
  • Higher intracellular accumulation of GT compared to AT was observed.

Conclusions:

  • GT exhibits significant antitumor effects against human lymphoma cells through enhanced mitochondrial ROS generation and activation of both intrinsic and extrinsic apoptotic pathways.
  • GT's selective toxicity towards cancer cells suggests its potential as a therapeutic agent in T cell lymphoma treatment.

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