Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress.
We have studied the potential effect against human malignant mesotheliomas (MM) of alpha-tocopheryl succinate (alpha-TOS), a redox-silent vitamin E analog with strong pro-apoptotic and anti-cancer activity. alpha-TOS at sub-apoptotic levels inhibited proliferation of MM cell lines, while being nontoxic to nonmalignant mesothelial cells. Because MM cells are typified by a highly metastatic phenotype, we investigated the effect of alpha-TOS on genes playing a major role in MM progression. Of these, alpha-TOS down regulated fibroblast growth factor (FGF)-1 and, in particular, FGF-2 on the transcriptional level in MM cells, and this was not observed in their nonmalignant counterparts. FGF-2 short interfering RNA suppressed proliferation of MM cells. Down-regulation of FGF-2 was likely because of inhibition of the egr-1 transcription activity that was decreased in MM cells via oxidative stress induced by alpha-TOS, as evidenced by EPR spectroscopy, whereas nonmalignant cells did not show this response. Treatment of MM cells with egr-1 short interfering RNA suppressed proliferation, which was overridden by exogenously added recombinant FGF-1 and, in particular, FGF-2. An analog of coenzyme Q targeted to mitochondria and superoxide dismutase overrode inhibition of MM cell proliferation by alpha-TOS as well as alpha-TOS-induced inhibition of egr-1-dependent transactivation. Finally, alpha-TOS significantly suppressed experimental MM in immunocompromised mice. Our data suggest that alpha-TOS suppresses MM cell proliferation by disrupting the FGF-FGF receptor autocrine signaling loop by generating oxidative stress and point to the agent as a selective drug against thus far fatal mesotheliomas.
Stapelberg
Michael
M
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, 4216 Queensland, Australia.
Gellert
Nina
N
Swettenham
Emma
E
Tomasetti
Marco
M
Witting
Paul K
PK
Procopio
Antonio
A
Neuzil
Jiri
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004277:DNA, Single-Stranded / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000503:physiopathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; D017382:Reactive Oxygen Species; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D014810:Vitamin E; D024505:Tocopherols