Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca₄Mn(DPDP)₅, MnDPDP and DPDP

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 [Ca₄Mn(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 Ca₄Mn(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 Ca₄Mn(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 Ca₄Mn(DPDP)₅. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca₄Mn(DPDP)₅ may be explained by redox interactions between Pt²⁺ and Mn²⁺ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt²⁺ presumably leads to oxidation of the Mn²⁺ from Ca₄Mn(DPDP)₅ as well as from Mn²⁺ in MnSOD and other endogenous sources. Thereafter, Mn³⁺ may be oxidized by peroxynitrite (ONOO^-) into Mn⁴⁺, 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 (O₂^•-) 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 Pt²⁺-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca₄Mn(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 Pt²⁺-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt²⁺ outcompetes Mn²⁺ and endogenous Zn²⁺ 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 Pt²⁺ by DPDP, which in turn suggests that Mn²⁺ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.