Naslov
Glioma growth suppression via modulation of cellular redox status by a lipophilic Mn porphyrin

Autori
Batinic-Haberle, Ines ; Keir, Stephen T. ; Rajić, Zrinka ; Tovmasyan, Artak ; Spasojević, Ivan ; Dewhirst, Mark W. ; Bigner Darell D.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Winter Brain SPORE Meeting / - , 2011

Skup
Winter Brain SPORE Meeting

Mjesto i datum
San Francisco (CA), Sjedinjene Američke Države, 27.01.2011. - 28.01.2011

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
Mn porphyrin; MnTnHex-2-PyP5+; oxidative stress; gliomas; SOD mimic; peroxynitrite; brain tumor

Sažetak
Mn porphyrins. Cationic Mn(III) N-substituted pyridylporphyrins are the most powerful mimics of superoxide dismutases and peroxynitrite scavengers. They also inhibit activation of major transcription factors HIF-1, NF-B, AP-1, SP-1, whereby downregulating expression of proteins involved in proliferative and apoptotic pathways. Such ability resulted in marked suppression of tumor growth in a mouse skin cancer [Zhao et al, Cancer Res 2005] and 4T1 breast cancer models [Moeller et al, Cancer Cell 2004]. The lipophilic Mn porphyrin (MnP), Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+, accumulates predominantly (>90%) in mitochondria (relative to cytosol) [Spasojevic et al, Free Radic Biol Med 2010]. Mitochondria are critical cellular compartments responsible for normal cell physiology, as well as for its failure. This MnP also crosses blood brain barrier, which is particularly relevant to the injuries of central nervous system [Doyle et al, Neuroscience 2009]. It has been further shown more efficacious in stroke and subarachnoid hemorrhage rodent models where clinically approved drugs failed [Sheng et al, J Pharmacol Exp Ther 2010 submitted]. It was also of remarkable efficacy in a rabbit cerebral palsy and mouse pain model. The mechanism of its action is at least in part related to the inhibition of cellular transcriptional activity, in particular to the suppression of NF-B, and in turn suppression of excessive inflammatory and immune responses. The exceptional ability of this and other cationic ortho Mn(III) N-alkylpyridylporphyrins to modulate cellular redox status is at the origin of the beneficial effects ; such capacity is best described with their exceptional potency in mimicing SOD enzymes. Cancer. It has been now fully understood that cancer is under continuous oxidative stress with poor antioxidant status, and thus very sensitive to the levels of reactive species. Tumor utilizes its “own” oxidative stress to signal the proliferation, but can undergo death when its oxidative stress is excessive – a redox paradox. The most powerful MnPs are able to equally effectively give and accept electrons, and can thus act as pro- and antioxidants, depending upon the levels of reactive species and endogenous antioxidants, site of their accumulation, and ratio of superoxide- to peroxide-removing enzymes. Two scenarios are thus possible when Mn porphyrin perturbs the fragile redox balance between reactive species and antioxidants which eventually leads to cell death: (1) the removal of reactive species that would prevent cell proliferation ; (2) or increased production of such species that would signal cell to undergo apoptosis. Both scenarios have already been exemplified. Mn porphyrin in gliomas. While mechanism of Mn porphyrin anticancer action is not fully understood, the effects are remarkable both in vitro and in vivo. Therefore, and because of its lipophilicity, MnTnHex-2-PyP5+ was tested in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED). When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP5+ caused significant (P ≤ 0.001) growth delays in D 245 MG, D-256 MG, D-341 MED, and D-456 MG xenografts. Growth delays for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MG. With mice bearing intracranial xenografts, MnTnHex-2-PyP5+ produced a statistically significant (P ≤ 0.001) increase in median mouse survival for 33% with D-256 MG, and 173% with D-341 MED cell line [Keir et al, Anticancer Agents Med Chem 2010]. The studies are in progress on D-245 MG, where MnTnHex-2-PyP5+ treatment is combined with radiation and temozolomide. MnTnHex-2-PyP5+ in its own right, produced only marginal effects with D-245 MG, but synergism was already detected when mice bearing subcutaneous glioma were treated with radiation + MnP. Future strategies. Another strategy for glioma therapy recently emerged and is supported with at least 4 arguments and several data sets: (1) MnP preferentially accumulates in 4T1 breast tumor [Spasojevic et al, Free Radic Res 2010, Tian et al, Cancer Biother Radiopharm 2010] ; (2) brain and spleen have the highest body levels of ascorbate [Mandl et al, Brit J Pharmacol 2009] ; (3) cancer cell preferentially uptakes ascorbate, utilizing overexpressed glucose transporter system, GLUT1for dehydroascorbate uptake, which is subsequently reduced to ascorbate by dehydroascorbate reductase [Verrax et al, Curr Med Chem 2009] ; and (4) MnP tumor accumulation is enhanced in the presence of ascorbate. When given along with ascorbate, MnP acts as pro-oxidant, i.e. as catalyst of ascorbate oxygen consumption, whereby superoxide, peroxide and hydroxyl radical production increases tumor oxidative stress to the extent that forces it to undergo apoptosis. The strategy has been already shown successful in vitro on 5 different cancer cell lines, in in vivo 4T1 breast cancer mouse study [Ye et al, Free Radic Biol Med 2009], and with SOD-deficient E. coli [Rajic et al, Free Radic Biol Med 2010]. Similar cancer in vivo and in vitro studies, where endogenous Fe porphyrins acted as catalysts of ascorbate –based reactive species production, was also reported by Levine et al [PNAS 2008]. Taken altogether, such data warrant exploration of MnP/ascorbate as treatment of gliomas. In conclusion, the ability of MnTnHex-2-PyP5+ to modulate cellular redox status and force cancer cell to chose death over survival, makes MnTnHex-2-PyP5+ in its own right, and in combination with radiation/temozolomide/ascorbate, a promising treatment of brain gliomas.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA