Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca 4 Mn(DPDP) 5 , MnDPDP and DPDP.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Antineoplastic Agents*/adverse effects ; Manganese*/adverse effects ; Oxaliplatin*/adverse effects ; Oxaliplatin*/pharmacology ; Peripheral Nervous System Diseases*/chemically induced ; Peripheral Nervous System Diseases*/metabolism ; Platinum*/adverse effects; Humans ; Edetic Acid/analogs & derivatives ; Nitrosative Stress/drug effects ; Oxidative Stress/drug effects ; Pyridoxal Phosphate/analogs & derivatives ; Pyridoxal Phosphate/pharmacology ; Pyridoxal Phosphate/metabolism ; Superoxide Dismutase/metabolism ; Clinical Trials, Phase III as Topic

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca 4 Mn(DPDP) 5 ; PledOx ^® ], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca 4 Mn(DPDP) 5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca 4 Mn(DPDP) 5 , a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca 4 Mn(DPDP) 5 . The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca 4 Mn(DPDP) 5 may be explained by redox interactions between Pt ²⁺ and Mn ²⁺ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt ²⁺ presumably leads to oxidation of the Mn ²⁺ from Ca 4 Mn(DPDP) 5 as well as from Mn ²⁺ in MnSOD and other endogenous sources. Thereafter, Mn ³⁺ may be oxidized by peroxynitrite (ONOO ^- ) into Mn ⁴⁺ , which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O 2 ^•- ) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt ²⁺ -associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca 4 Mn(DPDP) 5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt ²⁺ -associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt ²⁺ outcompetes Mn ²⁺ and endogenous Zn ²⁺ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt ²⁺ by DPDP, which in turn suggests that Mn ²⁺ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

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XXXX Karlsson-Tuner Invest AS; 001 Karlsson-Tuner Invest AS

Keywords: MnSOD mimetics; calmangafodipir; chelation therapy; mangafodipir; manganese; nitrosative stress; oxaliplatin-associated CIPN; oxidative stress; platinum

0 (Antineoplastic Agents)
9G34HU7RV0 (Edetic Acid)
42Z2K6ZL8P (Manganese)
P28BIW0UTB (N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid)
04ZR38536J (Oxaliplatin)
49DFR088MY (Platinum)
5V5IOJ8338 (Pyridoxal Phosphate)
EC 1.15.1.1 (Superoxide Dismutase)

Date Created: 20240427 Date Completed: 20240427 Latest Revision: 20240513

20240513

PMC11050347

10.3390/ijms25084347

38673932