H 2 O 2 -Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways

摘要

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 - , H 2 O 2 , H 2 S, CO 3 ?- , 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- κ B and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP 5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP 5+ (BMX-001), and MnTnHex-2-PyP 5+ , 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-PyP 5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP 5+ is in Phase II clinical trial on atopic dermatitis and itch. We have dedicated our review manuscript to a great colleague, dear friend, and exceptional scientist—Margaret Tome—who greatly influenced how we presently understand the in vivo mechanism of action of Mn porphyrin-based SOD mimics.