H₂O₂‐Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways

Abstract

Mn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3•-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.

MnTnHex-2-PyP5+, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways

“…Redox imbalance in the tumor is particularly relevant during tumor growth and neovascularization. Cationic Mn(III) meso -tetrakis( N -n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP 5+ ;MnHex), a potent lipophilic mimic of the family of porphyrin-based superoxide dismutases (SOD), has been shown to reduce oxidative damage by directly or indirectly reducing the levels of reactive species, thereby restoring the cellular physiological redox state [ 1 , 2 , 3 , 4 , 5 ]. Its analog, MnTnBuOE-2-PyP 5+ [Mn(III) meso -tetrakis( N -n-butoxyethylpyridinium-2-yl)porphyrin, BMX-001], is in four clinical trials as radioprotectant of normal tissue and tumor radio- and chemosensitizer [ 6 , 7 ].…”

Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins—Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions

“…Our studies taught us that ortho Mn porphyrins are able to promote the HA degradation in the presence of Cu(II) [or Fe(III)] and ascorbate. Such knowledge increases our insight into their anticancer therapeutic potential [22][23][24][25]. Scheme 1.…”

Preservation of neurocognitive function in the treatment of brain metastases

“…Recently, development of manganese porphyrin compounds that alter the redox biology of mitochondria has generated interest as possible dual tumor radiosensitizers and normal tissue radioprotectors. 93 Preclinical findings of preserved tumor control and neuroprotection with enhanced cognitive function following irradiation in mice spawned clinical trials in several cancer types, including brain metastases 87 (NCT03608020). The role of GSK-3beta inhibition as a general neuroprotection strategy that prevents radiation necrosis 88 is also exciting, and some clinical trial data exist for tideglusib in Alzheimer’s disease patients.…”