Related Experiment Video
Updated: Aug 23, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Ras inhibition amplifies cisplatin sensitivity of human glioblastoma
Samantha Messina1, Carlo Leonetti, Giorgia De Gregorio
1Dipartimento di Patologia Molecolare, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
Abstract:
Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway affects the response to cisplatin in malignant gliomas. We found an enhanced sensitivity to cisplatin of two glioblastoma cell lines expressing dominant negative Ras. Moreover, DN-Ras expressing cells, implanted in nude mice, resulted in being extremely sensitive to cisplatin. The growth of all the tumors was significantly inhibited by combining DN-Ras adenovirus infection with cisplatin treatment. The majority of glioma cells expressing DN-Ras underwent apoptosis in response to cisplatin. In vivo, DN-Ras alone did not influence the growth of tumors, suggesting that the effects of Ras-inhibition observed in vitro could not be extrapolated in vivo. The survival signal pathway transduced by Ras was essentially mediated by inhibition of caspase-9 cleavage via PI3K/Akt.
Insights
Inhibiting the Ras pathway enhances glioblastoma cell sensitivity to cisplatin chemotherapy. Combining dominant-negative Ras (DN-Ras) with cisplatin significantly reduced tumor growth and increased apoptosis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant gliomas often exhibit resistance to chemotherapy.
- Receptor tyrosine kinase (RTK)-regulated signaling pathways, particularly involving p21-Ras, are implicated in this resistance.
- Understanding mechanisms to overcome chemoresistance is crucial for improving glioma treatment outcomes.
Purpose of the Study:
- To investigate the impact of inhibiting the Ras pathway on the response of malignant gliomas to cisplatin chemotherapy.
- To determine if targeting the Ras pathway can re-sensitize glioblastoma cells to cisplatin treatment.
Main Methods:
- Utilized glioblastoma cell lines engineered to express dominant-negative Ras (DN-Ras).
- Assessed cisplatin sensitivity in vitro and in vivo using xenograft models in nude mice.
- Investigated the role of the PI3K/Akt/caspase-9 pathway in Ras-mediated survival signals.
Main Results:
- Glioblastoma cells expressing DN-Ras demonstrated enhanced sensitivity to cisplatin in vitro.
- Tumor growth in vivo was significantly inhibited when combining DN-Ras adenovirus infection with cisplatin treatment.
- DN-Ras expression led to increased cisplatin-induced apoptosis in glioma cells.
- DN-Ras alone did not affect tumor growth in vivo, indicating context-dependent effects of Ras inhibition.
- Ras-mediated survival signaling was found to involve PI3K/Akt inhibition of caspase-9 cleavage.
Conclusions:
- Inhibition of the Ras pathway, using DN-Ras, can overcome cisplatin resistance in malignant gliomas.
- Combination therapy of Ras pathway inhibition and cisplatin shows significant therapeutic potential for glioblastoma.
- The PI3K/Akt pathway plays a key role in Ras-mediated chemoresistance by inhibiting apoptosis.
