Skip to main content Accessibility help
×
Home

08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis

  • S. Shojaei, J. Alizadeh, J. Thliveris, N. Koleini, E. Kardami, G.M. Hatch, Fr. Xu, S. Hombach-Klonisch, T. Klonisch and S. Ghavami...

Abstract

Glioblastoma multiforme (GBM) is the deadliest brain tumor with an approximate 14 month survival rate after diagnosis and treatment. Temozolomide (TMZ), the chemotherapeutic drug of choice for GBM, is an alkylating agent that causes DNA damage. TMZ treatment results in the induction of apoptosis in GBM cells, however, it induces autophagy and consequently chemoresistance. Statins are mevalonate (MEV) cascade inhibitors with beneficial effects on the enhancement of the survival rate of patients with different types of cancer. Here, we determined the effect of simvastatin (Simva), a blood brain barrier permeable statin, on the sensitization of GBM cells to TMZ induced apoptosis through inhibition of autophagy flux. We pretreated two GMB cell lines, U251 and U87 cells, with low doses of Simva (1 and 2.5 M, respectively) with or without different intermediates of the mevalonate cascade and then treated cells with TMZ (100 M) for 48-96 hrs. A signficiantly reduced viability and increased in the population of apoptotic dead cells were observed in GBM cells treated with the Simva-TMZ compared to cells treated with TMZ alone. Addition of MEV, Farnesyl pyrophosphate, Geranylgeranyl pyrophosphate and cholesterol did not attenuate these effects significantly. Sima-TMZ treatment did not alter the total cholesterol pool in U87 and U251 cells compared to controls. Western blot analysis, immunocytochemistry and transmission electron microscopy revealed that Simva-TMZ inhibited autophagic flux. Overall, the results suggest that sensitization of GBM cells to TMZ-induced apoptosis by Simva is independent on the cholesterol biosynthetic pathway but may involve inhibition of autophagy.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis
      Available formats
      ×

Copyright

Corresponding author

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed