Identification of Experimental Prooxidants Targeting the Redox Vulnerability of Malignant Melanoma

Persistent Link:
http://hdl.handle.net/10150/293427
Title:
Identification of Experimental Prooxidants Targeting the Redox Vulnerability of Malignant Melanoma
Author:
Cabello, Christopher Michael
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Cumulative evidence suggests that redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. According to this emerging mechanism, pharmacological prooxidants may induce deviations from redox homeostasis causing cytotoxicity confined to malignant cells already at a high set point of constitutive oxidative stress leading to functional impairment, cell cycle arrest, and cell death. In contrast, the same prooxidant deviation from redox homeostasis is tolerated by nonmalignant cells that operate at a lower redox set point. This work focuses on experimental redox drug discovery targeting metastatic melanoma cells by pursuing the following specific aims: I. To identify drug-like lead compounds containing redox-directed pharmacophores for prooxidant intervention targeting melanoma in relevant models of the human disease. II. To investigate the molecular mechanism of action underlying antimelanoma activity of our lead compounds comprising Michael acceptors [cinnamaldehyde (CA) and 2,6-dichlorophenolindophenol (DCPIP)] and endoperoxides [dihydroartemesinin (DHA)]. III. To explore the therapeutic potential of drug-like electrophiles for non-melanoma indications including skin photoprotection and genotype-directed cancer chemotherapy. First, we have explored the possibility that prooxidant dietary constituents containing an electrophilic Michael acceptor pharmacophore may display chemotherapeutic activity. Focusing on the cinnamon-derived Michael acceptor CA we have demonstrated significant anti-melanoma activity of this dietary prooxidant observed in vitro and in vivo. Second, we have demonstrated that the synthetic quinoneimine and redox dye DCPIP targets human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. Efficacy against tumors with low NQO1 enzymatic activity including those displaying the human homozygous NQO1*2 missense genotype suggests feasibility of DCPIP-based genotype-directed redox intervention. Third, we demonstrated that the endoperoxide-based antimalarial DHA may serve as an experimental redox chemotherapeutic that selectively induces iron-dependent melanoma cell apoptosis without compromising viability of primary human melanocytes. Given the causative role of redox dysregulation in melanoma and the shortage of efficacious agents currently available, it seems that the emerging therapeutic potential of redox-directed chemotherapeutics for melanoma intervention deserves further evaluation.
Type:
text; Electronic Dissertation
Keywords:
Cinnamaldehyde; Dichlorophenolindophenol; Dihydroartemesinin; Melanoma; Redox; Pharmaceutical Sciences; Cancer
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmaceutical Sciences
Degree Grantor:
University of Arizona
Advisor:
Wondrak, Georg T.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleIdentification of Experimental Prooxidants Targeting the Redox Vulnerability of Malignant Melanomaen_US
dc.creatorCabello, Christopher Michaelen_US
dc.contributor.authorCabello, Christopher Michaelen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractCumulative evidence suggests that redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. According to this emerging mechanism, pharmacological prooxidants may induce deviations from redox homeostasis causing cytotoxicity confined to malignant cells already at a high set point of constitutive oxidative stress leading to functional impairment, cell cycle arrest, and cell death. In contrast, the same prooxidant deviation from redox homeostasis is tolerated by nonmalignant cells that operate at a lower redox set point. This work focuses on experimental redox drug discovery targeting metastatic melanoma cells by pursuing the following specific aims: I. To identify drug-like lead compounds containing redox-directed pharmacophores for prooxidant intervention targeting melanoma in relevant models of the human disease. II. To investigate the molecular mechanism of action underlying antimelanoma activity of our lead compounds comprising Michael acceptors [cinnamaldehyde (CA) and 2,6-dichlorophenolindophenol (DCPIP)] and endoperoxides [dihydroartemesinin (DHA)]. III. To explore the therapeutic potential of drug-like electrophiles for non-melanoma indications including skin photoprotection and genotype-directed cancer chemotherapy. First, we have explored the possibility that prooxidant dietary constituents containing an electrophilic Michael acceptor pharmacophore may display chemotherapeutic activity. Focusing on the cinnamon-derived Michael acceptor CA we have demonstrated significant anti-melanoma activity of this dietary prooxidant observed in vitro and in vivo. Second, we have demonstrated that the synthetic quinoneimine and redox dye DCPIP targets human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. Efficacy against tumors with low NQO1 enzymatic activity including those displaying the human homozygous NQO1*2 missense genotype suggests feasibility of DCPIP-based genotype-directed redox intervention. Third, we demonstrated that the endoperoxide-based antimalarial DHA may serve as an experimental redox chemotherapeutic that selectively induces iron-dependent melanoma cell apoptosis without compromising viability of primary human melanocytes. Given the causative role of redox dysregulation in melanoma and the shortage of efficacious agents currently available, it seems that the emerging therapeutic potential of redox-directed chemotherapeutics for melanoma intervention deserves further evaluation.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCinnamaldehydeen_US
dc.subjectDichlorophenolindophenolen_US
dc.subjectDihydroartemesininen_US
dc.subjectMelanomaen_US
dc.subjectRedoxen_US
dc.subjectPharmaceutical Sciencesen_US
dc.subjectCanceren_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorWondrak, Georg T.en_US
dc.contributor.committeememberDorr, Roberten_US
dc.contributor.committeememberGerner, Eugeneen_US
dc.contributor.committeememberZhang, Donnaen_US
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