Synergistic anti-tumoral effect of paclitaxel (Taxol)+AS101 in a murine model of B16 melanoma: association with ras-dependent signal-transduction pathways

Int J Cancer. 2000 Apr 15;86(2):281-8. doi: 10.1002/(sici)1097-0215(20000415)86:2<281::aid-ijc20>;2-x.


Optimal doses of paclitaxel (Taxol) combined with the immunomodulator AS101, previously shown to have anti-tumoral 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.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Bone Marrow / pathology
  • Cell Cycle
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Ethylenes / administration & dosage*
  • Male
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Neoplasm Transplantation
  • Paclitaxel / administration & dosage*
  • Paclitaxel / toxicity
  • Proto-Oncogene Proteins c-raf / metabolism
  • Signal Transduction*
  • Spleen / pathology
  • ras Proteins / physiology*


  • Antineoplastic Agents, Phytogenic
  • Ethylenes
  • ammonium trichloro(dioxoethylene-O,O'-)tellurate
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 1
  • ras Proteins
  • Paclitaxel