Pharmacological Ascorbate Enhances Chemo-Radio-Sensitization in Brain and Lung Cancer

Allen, Bryan G.; Sibenaller, Zita A.; Cullen, Joseph J.; Buettner, Garry R.; Welsh, Jessemae L.; Wagner, Brett A.; Erve, Thomas J van't; Buatti, John M.; Carlisle, Thomas; Smith, Mark C.; Walsh, Susan A.; Bayouth, John E.; Tennapel, M.J.; Spitz, Douglas R.

doi:10.1016/j.freeradbiomed.2012.10.099

Cited by 6 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This reasoning is the same as the one behind the use of other H 2 O 2 -producing strategies: radio- and chemotherapy. Oxidation of ascorbate at the expense of endogenous metalloproteins has already been employed in clinical trials in patients with pancreatic cancer [61,62] . The use of Mn porphyrin, MnTE-2-PyP 5+ and analogs of similar redox properties (MnTnHex-2-PyP 5+ , MnTnBuOE-2-PyP 5+ ), optimized for ascorbate oxidation, has been reported by us [3,6,41,43,44] and subsequently by others to bear therapeutic potential [40,42,63] .…”

Section: Scheme Imentioning

confidence: 99%

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

2015

View full text Add to dashboard Cite

Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2•− dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also. Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2•− dismutation process, the most powerful Mn porphyrin-based SOD mimics reduce and oxidize O2•− with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants. Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2•− dismutation parallels all other reactivities (such as ONOO− reduction) and in turn their therapeutic efficacies. Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox-active therapeutics.

show abstract

Section: Scheme Imentioning

confidence: 99%

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

2015

View full text Add to dashboard Cite

show abstract

“…Osmium tetroxide, OsO 4 An aqueous solution of OsO 4 has a SOD-like potency which is comparable to that of cerium dioxide. However, it is a very toxic compound.…”

Section: Fe(iii) Porphyrinsmentioning

confidence: 99%

“…Buettner's group has also reported that ascorbate acts as a radiosensitizer in pancreatic cancer via production of reactive species (4,290). The group is further exploring the role of transition metals and their porphyrin complexes on ascorbateinduced cytotoxicity in cancer (220).…”

mentioning

confidence: 99%

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

Batinić‐Haberle

Tovmasyan

Roberts

et al. 2014

Antioxidants & Redox Signaling

202

458

View full text Add to dashboard Cite

Significance: Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O 2 $ -; no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored. Recent Advances: Structure-activity relationship (half-wave reduction potential [E 1/2 ] versus log k cat ), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E 1/2 of *+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O 2 $ -) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants. Critical Issues: Although log k cat (O 2 $ -) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor jB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells. Future Directions: Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs. Antioxid. Redox Signal. 20, 2372Signal. 20, -2415

show abstract

“…The explanation that fits best the experimental data is as follows. Reactions [3]- [5] [7])/or by Mn II P (Eqs. [8] and [9]) in a two-electron process mimicking the first step of a catalase-like activity of MnPs (170), giving rise to high-valent and highly potent oxidants-Mn(IV) or Mn(V) oxo porphyrins.…”

Section: From the Catalysis Of Omentioning

confidence: 99%

“…Anticancer radiation and chemotherapies take advantage of the inability of tumor to cope with excessive levels of RS by further increasing its oxidative stress. Recently, combined with radio-and/or chemotherapy, ascorbate progressed to clinical trials with pancreatic (NCT02905578), brain (NCT02344355), and lung cancer patients (NCT02420314) (3,60,189). The oxidation of ascorbate, catalyzed by metal complexes, gives rise to large quantities of H 2 O 2 (Eq.…”

Section: Therapeutic Effects Of Mn Porphyrinsmentioning

confidence: 99%

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

Batinić‐Haberle

Tovmasyan

Spasojević

2018

Antioxidants & Redox Signaling

110

195

View full text Add to dashboard Cite

show abstract

Pharmacological Ascorbate Enhances Chemo-Radio-Sensitization in Brain and Lung Cancer

Cited by 6 publications

References 0 publications

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

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

Contact Info

Product

Resources

About