Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury

Abstract

Studies that simultaneously explore differential effects in same animal are lacking, while they are essential for understanding of extremely intricate interactions of metal-based drugs with complex cellular networks of normal and cancer cells/tissues.

Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide

“…Although the most common oxidation states of manganese range from +2 to +7, in the MnPs they range from +2 to +5 Mn(II) to Mn(IV) [33]. The hallmark of MnP-catalyzed H 2 O 2 production from a reductant such as ascorbate and O 2 is the one-electron redox cycling of manganese between Mn(III)P and Mn(II)P [13], which is favored over a wide range of pH from~3 to 10 [34]. In this one-electron redox reaction the Soret peak blue-shifts from 454 to 438 nm and the Q band red-shifts from 560 to 565 nm as the MnP is reduced from Mn(III)P to Mn(II)P [35].…”

“…Most notable are three MnPs; MnTE-2-PyP 5+ (MnTE, AEOL10113, BMX-010), MnTnHex-2-PyP 5+ (MnHex), and MnTnBuOE-2-PyP 5+ (MnBuOE, BMX-001), that closely mimic the reduction potential (E 1 2 ) of the endogenous antioxidant enzyme, superoxide dismutase (SOD;~+300 mV vs the normal hydrogen electrode (NHE)) [10,11]. Although these MnPs are excellent SOD mimetics, they lack the tertiary structure that enables the high specificity of SOD toward superoxide and they react with other compounds such as peroxynitrite, carbonate radical, nitric oxide, peroxide, small aminothiols or protein thiols, and hypochlorite [12,13].…”

“…As this cycle is repeated, the superoxide that is generated either spontaneously, or catalyzed by SOD or MnPs, is dismuted to O 2 and H 2 O 2 . The resultant H 2 O 2 is used by MnP in a catalytic cycle where regulatory protein cysteines, that may mediate cytoprotection in healthy cells and/or initiate apoptotic reactions in malignant ones, are oxidized [12,13].…”

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

“…As shown in Figure 6A,B, MnTE decreased H 2 S and increased polysulfides in both cell lines consistent with previous observations (cf. Figures 1 and 5 The biological actions of MnPs are thought to be due to redox cycling where oxidized Mn(III)P is reduced by a reductant such as ascorbic acid (AA) and then re-oxidized by oxygen which generates superoxide [4,[8][9][10]. The superoxide then spontaneously (or catalyzed by SOD or MnPs if present) dismutes to form peroxide and oxygen with the ultimate biological effects exerted by the peroxide.…”

“…This activates cytoprotective antioxidant defenses in healthy cells, presumably mediated to a large extent through the peroxidation of Keap-1 which frees it from Nrf2 allowing the latter to translocate to the nucleus and activate the antioxidant defenses. Peroxide also creates lethal oxidative stress in malignant cells [1,4]. However, unlike their ability to dismute superoxide, in this instance MnPs are believed to produce H 2 O 2 by MnP cycling between one-electron reduction by a cellular reductant such as ascorbic acid (AA) and one-electron oxidation by oxygen.…”