Synergistic anti-tumoral effect of paclitaxel (taxol)+AS101 in a murine model of B16 melanoma: Association with ras-dependent signal-transduction pathways
✍ Scribed by Yona Kalechman; Dan L. Longo; Raphael Catane; Adi Shani; Michael Albeck; Benjamin Sredni
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- French
- Weight
- 206 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Optimal doses of paclitaxel (Taxol) combined with the immunomodulator AS101, previously shown to have antitumoral effects, administered to B16 melanoma-bearing mice decreased tumor volume and resulted in over 60% cure. Paclitaxel؉AS101 directly inhibited the clonogenicity of B16 melanoma cells in a synergistic, dose-dependent manner. We suggest that this results from both reduced paclitaxel-induced bone marrow toxicity and induction of differential signal-transduction pathways, which lead to apoptosis of tumor cells. Paclitaxel؉AS101 synergistically activated c-raf-1 and MAPK ERK1 and ERK2. This activation was essential for the synergistic induction of p21 waf protein. Cell-cycle analysis of B16 cells treated with both compounds revealed an increased accumulation in G 2 M, though AS101 alone produced significant G 1 arrest. These activities were ras-dependent. AS101؉paclitaxel induced significant synergistic phosphorylation (inactivation) of the anti-apoptotic protein Bcl-2. Whereas phosphorylation of Bcl-2 by paclitaxel was raf-dependent only, the synergistic effect of both compounds together was ras-, raf-and MAPK-dependent. No effect of the combined treatment on Bax protein expression was observed. We suggest that AS101 renders more cells susceptible to Bcl-2 phosphorylation by paclitaxel, possibly by increasing the accumulation of paclitaxel-induced cells in G 2 M. Exposure of B16 cells to clinically achievable concentrations of paclitaxel؉AS101 increased the rate of apoptosis of treated cells. Apoptosis induced by AS101 alone was both raf-and MAPK-dependent, while that induced by paclitaxel was raf-dependent only. Int.