Naslov
Mechanistic Considerations of the Therapeutic Effects of Mn Porphyrins, Commonly Regarded as SOD Mimics, in Anticancer Therapy: Lessons from Brain and Lymphoma Studies

Autori
Batinic-Haberle, Ines ; Tovmasyan, Artak ; Weitner, Tin ; Rajic, Zrinka ; Keir, Stephen T. ; Huang, Ting-Ting ; Leu, David ; Weitzel, Douglas P. H. ; Beausejour, Christian M. ; Miriyala, Sumitra ; Roberts, Emily R. H ; Dewhirst, Mark W. ; St. Clair, Daret ; Leong, Kam W. ; Spasojevic, Ivan ; Piganelli, Jon ; Tome, Margaret

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

Izvornik
Free Radical Biology Medicine / - , 2013, S120-S121

Skup
SFRBM's 20th Annual meeting

Mjesto i datum
San Antonio (TX), Sjedinjene Američke Države, 20.11.2013. - 24.11.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Mn pyridylporphyrin; MnTnBuOE-2-PyP5+; lymphoma; brain tumor; SOD mimic

Sažetak
Mn(III) ortho N-substituted pyridylporphyrins (MnPs) are among the most potent SOD mimics. Their SOD activity is an excellent measure of their therapeutic efficacy. in addition to anti-oxidative effects, pro-oxidative actions of MnPs contribute to their therapeutic efficacy (see Tovmasyan et al, abstract). Within the class of water-soluble MnPs of high kcat(O2 􀁸􀀐), MnTnBuOE-2- PyP5+(BuOE2) and (MnTnHex-2-PyP5+(Hex2) bear high lipophilicity. They distribute into all organs, including brain (see Spasojevic et al, abstract). After 7 days of sc-injections at 2×1mg/kg/day, the mouse hippocampus concentrations of BuOE2 and Hex2 were 85 nM and 58 nM, and cortex levels 14 and 31 nM. Mitochondria/cytosol ratios of BuOE2 and Hex2 are 3.2 and 3.6 in mouse heart and 2.5 and 1.9 in brain, and they mimic mitochondrial MnSOD in several studies (see Holley et al, abstract). MnP localization in hippocampal and brain mitochondria protect neurogenesis and neurocognitive function from radiation (RT). Treatment of RT-mice with Hex2 rescued neurosphere counts in p16INK4a-dependent manner. Further, there was a significantly higher number of immature neurons in the subgranular zone of hippocampal dentate gyrus in the group treated with BuOE2 vs saline group. Both MnPs exhibited radioand chemosensitization in sc xenograft Balb/c-nu/nu mouse of D- 245MG glioblastoma multiforme. Although significance in tumor growth delay was not achieved in the same mouse model using D-341MED pediatric medulloblastoma, the addition of Hex2 altered several pathways that could inhibit tumor growth and metastasis: metastasis (ctss, cathepsin L, becn1, beclin1) ; apoptosis, NF-􀁎B (Nfkb1, Bcl211, Bcl2) ; PI3kinase, mTOR (Rsp6kb) ; and protein translation (EIF5b and Rsp6kb1). Brain tumor and lymphoma data show that at least one of the major anticancer mechanisms of MnP is pro-oxidative, leading to glutathionylation (with H2O2 and GSH) of NF-􀁎B, as well as of enzymes of bioenergetic pathways (see Jaramillo et al, abstract) resulting in their inactivation. Excessive production of cytotoxic H2O2 by MnP/reductant (ascorbate, thiols), or MnP/chemotherapy or MnP/RT, could elevate the already existing cancer oxidative stress to a level which would cause its death. Such chemotherapeutic approach presents a novel anticancer strategy.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

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