Synergistic anti-tumoral effect of paclitaxel (Taxol)+AS101 in a murine model of B16 melanoma: association with ras-dependent signal-transduction pathways.
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.
Kalechman
Y
Y
C.A.I.R. Institute, The Marilyn Finkler Cancer Research Center, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Longo
D L
DL
Catane
R
R
Shani
A
A
Albeck
M
M
Sredni
B
B
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005030:Ethylenes / Q000008:administration & dosage*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000633:toxicity; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D018631:ras Proteins / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D005030:Ethylenes; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D018631:ras Proteins; D017239:Paclitaxel