The antioxidant phenylaminoethyl selenide reduces doxorubicin-induced cardiotoxicity in a xenograft model of human prostate cancer

Kang, Jeong Yeon; Costyn, Leah J.; Nagy, Tamás; Cowan, Elizabeth A.; Oldham, Charlie D.; May, Sheldon W.; Arnold, Robert D.

doi:10.1016/j.abb.2011.08.008

Cited by 14 publications

(19 citation statements)

References 42 publications

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“…Cardiomyocytes were incubated with increasing concentrations of DOX (1, 10 and 50 μM), in presence of 1 μM PAESe for 24 hr. Cells were then treated with 2′–7′-dichlorodihydrofluorescein diacetate (H 2 DCFDA) (Molecular Probes) and washed after 30 min with PBS (13, 25). Cells were then lifted mechanically, rinsed with PBS and centrifuged for 5 min (1,000 × g ).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies showed that PAESe reduced DOX-mediated neutrophil and macrophage cardio-infiltration when compared to DOX treated animals (13). Surprisingly, tumor growth (volume) from PAESe treated mice was similar to DOX treatment groups.…”

Section: Introductionmentioning

confidence: 93%

“…In that study, the growth inhibitory effects of DOX were not altered by PAESe (up to 10 μM) on PC-3 cells in vitro, and PAESe decreased formation of intracellular reactive free radicals from DOX in a dose-dependent manner. Most interestingly, findings from that study suggested that PAESe exerted antitumor activity in an in vivo human prostate adenocarcinoma (PC-3) tumor xenograft mouse model; however this observation and the mechanism(s) of this effect were not clear and required further examination (13). …”

Section: Introductionmentioning

confidence: 98%

“…1B) is a selenium-containing antioxidant that exerts its activity by reacting with metabolic oxidants such as peroxide, peroxynitrite anion and hydroperoxides using selenium redox recycling (9–12). Previously, we demonstrated that PAESe had a protective effect against DOX-induced cardiotoxicity using in vitro and in vivo mouse models of human prostate (PC-3) cancer (13). In that study, the growth inhibitory effects of DOX were not altered by PAESe (up to 10 μM) on PC-3 cells in vitro, and PAESe decreased formation of intracellular reactive free radicals from DOX in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…To gain mechanistic insights into the prolonged survival and cardioprotective activity, previously observed (13), in vitro studies using rat derived cardiomyocytes (H9C2) cells were used to examine effect of PAESe on DOX-mediated toxicity, generation of reactive oxygen species (ROS) and development of cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, Antitumor and Cardioprotective Effects of Liposome-Encapsulated Phenylaminoethyl Selenide in Human Prostate Cancer Rodent Models

et al. 2014

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Purpose Cardiotoxicity associated with the use of doxorubicin (DOX), and other chemotherapeutics, limits their clinical potential. This study determined the pharmacokinetics and antitumor and cardioprotective activity of free and liposome encapsulated phenyl-2-aminoethyl-selenide (PAESe). Methods The pharmacokinetics of free PAESe and PAESe encapsulated in liposomes (SSL-PAESe) were determined in rats using liquid chromatography tandem mass-spectrometry. The antitumor and cardioprotective effects were determined in a mouse xenograft model of human prostate (PC-3) cancer and cardiomyocytes (H9C2). Results The encapsulation of PAESe in liposomes increased the circulation half-life and area under the drug concentration time profile, and decreased total systemic clearance significantly compared to free PAESe. Free- and SSL-PAESe improved survival, decreased weight-loss and prevented cardiac hypertrophy significantly in tumor bearing and healthy mice following treatment with DOX at 5 and 12.5 mg/kg. In vitro studies revealed PAESe treatment altered formation of reactive oxygen species (ROS), cardiac hypertrophy and gene expression, i.e., atrial natriuretic peptide and myosin heavy chain complex beta, in H9C2 cells. Conclusions Treatment with free and SSL-PAESe exhibited antitumor activity in a prostate xenograft model and mitigated DOX-mediated cardiotoxicity.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics, Antitumor and Cardioprotective Effects of Liposome-Encapsulated Phenylaminoethyl Selenide in Human Prostate Cancer Rodent Models

et al. 2014

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Selenium-Based Drug Design

May

2015

Topics in Medicinal Chemistry

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The biochemistry, pharmacology and epidemiology of selenium and selenium-containing compounds continue to be subjects of considerable interest from the viewpoint of public health. Selenium has a long history of association with human health and disease, and we now recognize that this element is an essential nutrient that is critical to key cellular processes. We now know that the selenoproteins constituting the human selenoproteome are encoded by 25 genes in the human genome, and much progress is being made in our understanding of selenium metabolism and the health effects of selenium metabolites in normal and disease states. The idea that selenium-containing dietary supplements might be effective in preventing disease has gone through both optimistic and pessimistic phases in recent years, and the future prospects for such a nutritional approach are unclear at the present time. In contrast, a significant number of promising efforts are underway that are aimed at designing and developing pharmaceutical agents that are selenium-based or that target specific aspects of selenium metabolism. This chapter focuses on some of these efforts to develop new selenium-based anticancer, antioxidant, antihypertensive, antiviral, immunosuppressive, and antimicrobial agents. While most of the efforts that entail designed organoselenium compoundsas opposed to inorganic selenium metabolites -are still at the preclinical stage, evidence is emerging that selenium-based compounds can operate via several beneficial biochemical and pharmacological mechanisms. Since our understanding of the biology, biochemistry and pharmacology of selenium and selenoproteins is rapidly expanding, we can anticipate that the coming years will bring further development of new selenium-based pharmaceutical agents with therapeutic potential against human diseases.

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