Cancer Center Papers

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Klotho pathways, myelination disorders, neurodegenerative diseases, and epigenetic drugs
(Mary Ann Liebert, Inc., 2020) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kanara, Iphigenia; Mavrakis, Anastasios N.; Pernokas, Julie; Pernokas, Mark; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G.; Zamboni, Robert J.; Kodukula, Krishna; Chen, Xiaohong
In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.
Epigenetic treatment of persistent viral infections
(Wiley, 2017-02-01) Moos, Walter H.; Pinkert, Carl A.; Irwin, Michael H.; Faller, Douglas V.; Kodukula, Krishna; Glavas, Ioannis P.; Steliou, Kosta
Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world’s population. Exploring the population diversity of the human microbiome and the effects its compositional variances have on the immune system, health, and disease are the subjects of intense investigational research and study. Among the collection of viruses, bacteria, fungi, and single-celled eukaryotes that comprise the human microbiome, the virome has been grossly understudied relative to the influence it exerts on human pathophysiology, much as mitochondria have until recently failed to receive the attention they deserve, given their critical biomedical importance. Fortunately, cellular epigenetic machinery offers a wealth of druggable targets for therapeutic intervention in numerous disease indications, including those outlined above. With advances in synthetic biology, engineering our body’s commensal microorganisms to seek out and destroy pathogenic species is clearly on the horizon. This is especially the case given recent breakthroughs in genetic manipulation with tools such as the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) gene-editing platforms. Tying these concepts together with our previous work on the microbiome and neurodegenerative and neuropsychiatric diseases, we suggest that, because mammalian cells respond to a viral infection by triggering a cascade of antiviral innate immune responses governed substantially by the cell’s mitochondria, small molecule carnitinoids represent a new class of therapeutics with potential widespread utility against many infectious insults.
Epigenetic treatment of dermatologic disorders
(Wiley, 2019-09) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kanara, Iphigenia; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G.; Kodukula, Krishna; Zamboni, Robert J.
Healthy skin protects us against a multitude of insults but injured or maladapted skin can lead to infection, inflammation or worse. Fortunately, naturally occurring bioactive products, many commonly found in olive oil and other plant and vegetable extracts,have shown utility in treating skin and related diseases as well as conditioning the skin to maintain its healthy function. Powerful agents targeting nuclear regulatory pathways continue to hold promise as new or repurposed therapies for a wide variety of ills and skin conditions. Epigenetic approaches that activate Nrf2 to effect detoxification, redox balance, DNA repair and mitochondrial function are noteworthy. Some of the disease applications being actively investigated range from eczema and psoriasis to skin cancer and diabetes-related wound healing to name just a few
Epigenetic treatment of neurodegenerative disorders: Alzheimer and Parkinson diseases
(Wiley-Blackwell, 2016-05-01) Irwin, Michael H.; Moos, Walter H.; Faller, Douglas V.; Steliou, Kosta; Pinkert, Carl A.
In this review we expand our discussion of epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt–Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy.
Epigenetic treatment of neuropsychiatric disorders: autism and schizophrenia
(John Wiley & Sons, Inc., 2016-03-01) Moos, Walter H.; Maneta, Eleni; Pinkert, Carl A.; Irwin, Michael H.; Hoffman, Michelle E.; Faller, Douglas V.; Steliou, Kosta
Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.
Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition
(Wiley-Blackwell, 2015-03-01) Parameshwaran, Kodeeswaran; Irwin, Michael H.; Steliou, Kosta; Suppiramaniam, Vishnu; Pinkert, Carl A.
Mitochondrial dysfunction is a key component of various aging-related pathologies of the brain that result in dementia. As such, it provides an important avenue in development of therapeutic interventions for a host of neurological disorders. A requirement for functional mitochondrial respiratory chain complex I (CI),in order to accomplish the normal physiological processes regulating memory,seems intuitive. In this study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day) was administered by oral gavage to female ICR mice (3-4 month-old) that were subsequently treated with the mitochondrial complex I inhibitor rotenone (400 mg/kg/day). After one week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a region of the brain that functions primarily in regulating memory formation. Electrophysiological recordings in live brain slices showed that long-term potentiation (LTP) was reduced by rotenone exposure (P<0.05), while pre-treatment with PMX-500FI maintained LTP similar to control levels (P>0.05). Potentiation during theta burst stimulation (TBS) was similar among treatment groups (P>0.05); however, neurotransmitter release, which increased in control mice after TBS, was lower in rotenone treated mice (P<0.05), and was accompanied by reduced basal synaptic transmission (P<0.05), increased pro-apoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P<0.05). For each of these determinations, pre-treatment with PMX-500FI alleviated the harmful effects of rotenone. These results illustrate that treatment with antioxidant PMX-500FI is protective against rotenone-induced impairment of neuronal bioenergetics in the mouse hippocampus, in regard to both excitatory synaptic physiology and pro-apoptotic signaling. The protective effect of PMX-500FI against rotenone-induced disruption of cellular bioenergetics may have important therapeutic implications for treating aging-related dementia and other diseases related to mitochondrial dysfunction and/or oxidative damage.
Bioprotective carnitinoids: lipoic acid, butyrate, and mitochondria-targeting to treat radiation injury: mitochondrial drugs come of age
(Wiley-Blackwell, 2015-06-01) Steliou, Kosta; Faller, Douglas V.; Pinkert, Carl A.; Irwin, Michael H.; Moos, Walter H.
Given nuclear-power-plant incidents such as the 2011 Japanese Fukushima-Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic-driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential–although further research and development is required to prove the effectiveness of this approach–to provide field-ready radiation-protective drugs.
Neuroprotective effects of carnitinoid compounds in rodent cellular and in vivo models of mitochondrial complex I dysfunction
(Mesford Publisher Inc, 2019-03-13) Steliou, Kosta
Rotenone-mediated mitochondrial complex I inhibition was used to model Parkinson’s disease-like syndrome in Lewis rats. Tyrosine hydroxylase immunolabeling demonstrated a decrease in the number of dopaminergic neurons as well as aberrant morphology in surviving neurons. Administration of carnitinoid compounds (synthetic lipoylcarnitine or butyrylcarnitine compounds) reduced dopaminergic neuronal cell loss with characteristic morphology observed in surviving neurons. In a rat primordial hippocampal cell line (H19-7/IGF-IR), rotenone treatment resulted in increased ROS and reduced cellular ATP, while co-treatment with lipoylcarnitine maintained ROS and ATP at control levels. These results illustrate the therapeutic potential of small-molecule carnitinoids in treating neurodegenerative diseases associated with mitochondrial dysfunction.
Epigenetic treatment of neurodegenerative ophthalmic disorders: an eye toward the future.
(2017) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Irwin, Michael H.; Kanara, Iphigenia; Pinkert, Carl A.; Powers, Whitney R.; Steliou, Kosta; Vavvas, Demetrios G.; Kodukula, Krishna
Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.
Telomeric DNA Induces Apoptosis and Senescence of Human Breast Carcinoma Cells
(BioMed Central, 2007-1-26) Yaar, Mina; Eller, Mark S.; Panova, Izabela; Kubera, John; Wee, Lee Hng; Cowan, Kenneth H.; Gilchrest, Barbara A.
INTRODUCTION. Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways. METHODS. The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos. RESULTS. Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells. CONCLUSION. By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies.
Aberrant Cytoplasm Localization and Protein Stability of SIRT1 is Regulated by PI3K/IGF-1R Signaling in Human Cancer Cells
(Ivyspring International Publisher, 2010-10-7) Byles, Vanessa; Chmilewski, Laura K.; Wang, Joyce; Zhu, Lijia; Forman, Lora W.; Faller, Douglas V.; Dai, Yan
SIRT1, an NAD-dependent histone/protein deacetylase, has classically been thought of as a nuclear protein. In this study, we demonstrate that SIRT1 is mainly localized in the nucleus of normal cells, but is predominantly localized in the cytoplasm of the cancer / transformed cells we tested. We found this predominant cytoplasmic localization of SIRT1 is regulated by elevated mitotic activity and PI3K/IGF-1R signaling in cancer cells. We show that aberrant cytoplasmic localization of SIRT1 is due to increased protein stability and is regulated by PI3K/IGF-1R signaling. In addition, we determined that SIRT1 is required for PI3K-mediated cancer cell growth. Our study represents the first identification that aberrant cytoplasm localization is one of the specific alternations to SIRT1 that occur in cancer cells, and PI3K/IGF-1R signaling plays an important role in the regulation of cytoplasmic SIRT1 stability. Our findings suggest that the over-expressed cytoplasmic SIRT1 in cancer cells may greatly contribute to its cancer-specific function by working downstream of the PI3K/IGF-1R signaling pathway.
Preventive strategies and research for ultraviolet-associated cancer
(National Institute of Environmental Health Sciences, 1995-11) Koh, H.K.
Ultraviolet (UV)-associated cancer is the most common cancer in the United States. Approximately 90% of nonmelanoma skin cancer and 65% of melanoma are attributable to UV exposure and theoretically could be eliminated by primary prevention measures. Safe sun strategy includes use of sunscreens, use of protective clothing, minimization of exposure from 10 A.M. to 3 P.M., and avoidance of tanning parlors. Although more definitive data in human populations on the effectiveness of sunscreens to prevent melanoma and skin cancer are needed, sunscreens are thought to reduce risk. Safe sun prevention must start in childhood and adolescence when people receive most of their UV exposure. Secondary prevention through professional and public education and early detection may further reduce melanoma mortality.

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