The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line

Elodie Josset1, Hélène Burckel, Georges Noël

  • 1Université de Strasbourg, Centre régional de Lutte contre le Cancer Paul Strauss, 3 rue de la Porte de l'Hôpital, F-67085 Strasbourg Cedex, France.

Insights

The combination of RAD001 and temozolomide effectively inhibits glioblastoma cell growth and enhances autophagic cell death. This multipronged approach, including radiotherapy, shows promise for treating glioblastoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Glioblastoma is an aggressive brain tumor with limited treatment options.
  • The mammalian target of rapamycin (mTOR) pathway is implicated in glioblastoma growth.
  • Temozolomide is a standard chemotherapy agent for glioblastoma.

Purpose of the Study:

  • To investigate the combined effects of RAD001 (an mTOR inhibitor) and temozolomide on glioblastoma U-87 cells in vitro.
  • To determine the impact of this combination on cell proliferation, apoptosis, and autophagic cell death.
  • To evaluate the potential synergy with gamma-ray irradiation.

Main Methods:

  • In vitro study using the glioblastoma cell line U-87.
  • Treatment with varying concentrations of temozolomide and RAD001.
  • Assessment of cell proliferation, apoptosis, and autophagy.
  • Combination therapy including gamma-ray irradiation.

Main Results:

  • Temozolomide progressively decreased cell proliferation, an effect amplified and prolonged by RAD001.
  • The combination induced significant autophagic cell death, with minimal apoptosis.
  • Combining RAD001, temozolomide, and gamma-ray irradiation enhanced overall cytotoxicity.

Conclusions:

  • RAD001 potentiates temozolomide-induced autophagy, a key mechanism of cell death in glioblastoma.
  • The combination of mTOR inhibition, chemotherapy, and radiotherapy offers a promising strategy for glioblastoma management.
  • This multipronged approach may improve outcomes for patients with glioblastoma.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...