Salvemini et al. reply
We would like to thank Dr. Arbiser for his pertinent comments on our manuscript. The rationale that reactive oxygen species are involved in cancer has been appreciated for quite some time in a number of areas. For example, Larry Oberley's pioneering work over the last twenty years or so has clearly shown that overexpression of MnSOD inhibits in vitro and in vivo growth of various tumor cells. In addition, and as correctly pointed out by Arbiser, reactive oxygen species can trigger the activation of certain transcription factors (such as NF-κB), which in turn induce genes that can cause transformation and increased angiogenesis. Reduction of reactive oxygen in these tumor cells leads to decreased angiogenesis. Therefore, removal of superoxide by a superoxide dismutase mimetic such as M40403 should, in theory, have antitumor effects. Our experiments show that when used at a single low dose, M40403 has no effect on tumor growth in vivo. As Arbiser correctly notes, increasing the doses of M40403 or manipulating the dosing regimen might have allowed M40403 to exert an antitumor effect. However, our experiments were not aimed at addressing whether M40403 has direct antitumor effects. Rather, we wanted to determine whether a low dose of M40403 would enhance the antitumor action of IL-2, which it did. In response to Arbiser's comment regarding direct antitumor potential of SOD mimetics, our hypothesis, which is currently being evaluated, is that SOD mimetics will attenuate tumor cell growth in vivo when the doses are increased and when the appropriate dosing regimens are identified. This hypothesis is based on the proliferative literature that points to superoxide as an important mediator of cancer, and on our own preliminary data indicating that M40403 (and other SOD mimetics) has direct antitumor effects in vitro. We also have data showing that M40403 inhibits epithelial growth factor–induced tumor cell proliferation through inhibition of NF-κB activation. In general, multiple pathways are used by superoxide to modulate oncogenesis. Removal of reactive oxygen species with a SOD mimetic is a viable therapeutic opportunity in cancer.
See “Role of manganese superoxide dismutase in cancer” by Jack L. Arbiser.
References
Samlowski, W.E. et al. A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects. Nat. Med. 9, 750–755 (2003).
Arbiser, J.L. et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc. Natl. Acad. Sci. USA 99, 715–720 (2002).
Govindarajan, B. et al. Malignant transformation of melanocytes to melanoma by constitutive activation of MAP kinase kinase signaling. J. Biol. Chem. 278, 9790–9795 (2003).
Cohen, C. et al. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin. Cancer Res. 8, 3728–3733 (2002).
Govindarajan, B. et al. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase. Mol. Med. 8, 1–8 (2002).
Church, S.L. et al. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc. Natl. Acad. Sci. USA 90, 3113–3117 (1993).
Ma, X. et al. Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination. Oncogene 20, 3703–3715 (2001).
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Salvemini, D., Samlowski, W. Reply to “Role of manganese superoxide dismutase in cancer”. Nat Med 9, 1103 (2003). https://doi.org/10.1038/nm0903-1103b
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DOI: https://doi.org/10.1038/nm0903-1103b
