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Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals

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Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/281588707 Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals ARTICLE in CURRENT DRUG TARGETS · SEPTEMBER 2015 Impact Factor: 3.02 CITATION READS 1 75 8 AUTHORS, INCLUDING: Marco Malavolta Elisa Pierpaoli INRCA Istituto Nazionale di Ricovero e Cura p… INRCA Istituto Nazionale di Ricovero e Cura p… 118 PUBLICATIONS 2,156 CITATIONS 20 PUBLICATIONS 150 CITATIONS SEE PROFILE SEE PROFILE Laura Costarelli Francesco Piacenza INRCA Istituto Nazionale di Ricovero e Cura p… INRCA Istituto Nazionale di Ricovero e Cura p… 50 PUBLICATIONS 854 CITATIONS 34 PUBLICATIONS 344 CITATIONS SEE PROFILE SEE PROFILE Available from: Marco Malavolta Retrieved on: 26 October 2015 Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals Marco Malavolta1*, Elisa Pierpaoli2, Robertina Giacconi1, Laura Costarelli1, Francesco Piacenza1, Andrea Basso1, Maurizio Cardelli2, Mauro Provinciali2 1 Nutrition and aging Centre, Scientific and Technological Pole, Italian National Institute of Health and Science on Aging (INRCA) 2 Advanced Technology Center for Aging Research, Scientific Technological Area, Italian National Institute of Health and Science on Aging (INRCA) *Corresponding Author: Nutrition and aging Centre, Scientific and Technological Pole, Italian National Institute of Health and Science on Aging (INRCA), via Birarelli 8, 60121, Ancona, Italy; Phone: +39-0718004113; Fax: +39- 071206791; email: [email protected] Abstract The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence-targeted health promoting nutraceuticals. Tocotrienols (T3s) and quercetin (QUE), albeit belonging to different phytochemical classes, display similar and promising effects “in vitro” when tested in normal and cancer cells. Both compounds have been shown to induce senescence and promote apoptosis in a multitude of cancer lines. Conversely, they display senescence delaying activity in primary cells and rejuvenating effects in senescent cells. More recently, QUE has been shown to display senolytic effects in some primary senescent cells, likely as a consequence of its inhibitory effects on specific anti-apoptotic genes (i.e. PI3K and other kinases). Senolytic activity has not been tested for T3s but part of metabolic and apoptotic pathways affected by these compounds in cancer cells overlap with those of QUE. This suggests that the rejuvenating effects of T3s and QUE on pre-senescent and senescent primary cells might be the net results of a senolytic activity on senescent cells and a selective survival of a sub-population of non-senescent cells in the culture. The meaning of this hypothesis in the context of adjuvant therapy of cancer and preventive anti-aging strategies with QUE or T3s is discussed. Keywords: Cellular Senescence, Cancer, Nrf2, Tocotrienols, Quercetin, endoplasmic reticulum stress, senolytic compounds Introduction Cellular senescence (CS) is a biological response to a variety of stresses that results in persistent growth arrest with a distinct morphological and biochemical phenotype [1]. It is currently considered a “barrier” to prevent malignant transformation and, consequently, a potent anti-cancer mechanism. Exploration of CS as a target to drive towards antitumor adjuvant therapies or age-related diseases preventive strategies by natural substances is currently gaining increasing interest. Cancer cells can be forced to undergo senescence by natural substances, with effects somewhat comparable to those obtained by genetic and epigenetic manipulations, anticancer drugs, and irradiation [1]. These effects have been shown after sustained exposure “in vitro” to a wide range of different substances that are paradoxically used also to obtain cytoprotective and chemopreventive adaptive responses in normal cells [2]. Interestingly, a recent revision of literature on modulators of cellular senescence “in vitro” [2] identifies quercetin (QUE) and tocotrienols (T3s) as the only two phytochemicals (excluding carnosine which is not a phytochemical) that display all the 3 senescence- targeted outcomes that are commonly tested in vitro: 1) induction of a senescent-like phenotype in cancer cells; 2) delay of senescence markers onset in normal primary cells; and 3) rejuvenation of senescent and pre- senescent cells. This similarity could appear as a paradox If we consider the structural and physical differences of T3s (belonging to the methyl-tocols class of phytochemicals) and QUE (belonging to the flavonols class of phytochemicals. However, there are multiple area of overlap in their biological activity that might help to explain their similar outcome in primary senescent and cancer cells. In the first part of this review, we describe in brief the phenomenon of cellular senescence and the similitude between cancer cells and senescent cells. We then describe the effects of QUE and T3s in cancer and cellular senescence and integrate this knowledge with a meta-analysis to propose a unique mechanism of action that might be used to form a rationale to design new interventions in cancer and aging. Cellular Senescence in Brief CS is usually defined as a status of growth arrest mediated by insensibility to mitogen stimuli, chromatin and secretome changes, and upregulation of particular tumor suppressor pathways [3-4]. Currently, the causes and mechanisms involved in the phenomenon of CS represent an intense area of investigation and most aspects are still unclear. It is known that a variety of cell-intrinsic and -extrinsic stresses can activate the CS program. These include DNA damage, oxidative stress, critical telomere shortening and damage, chronic mitogenic signaling, oncogene activation and inactivation, loss of tumor suppressors, nucleolar stress, epigenetic changes and others [5]. The pathways and hallmarks shared by these processes have multiple areas of overlap that usually involve p53-p21 and p16-Rb pathways. Moreover, a persistent DNA damage response (DDR) stimulated by unrepaired DNA lesions appears in several experimental models of CS [6]. In replicative senescence, critical shortened telomeres are recognized as DNA breaks with subsequent stabilization of p53 and induction of senescence [7]. Stress and oncogene induced senescence work mainly through the activation of p16, but an interplay between p53 and p16 pathways has been frequently reported [8], so that p16 is currently considered a biomarker of aging [9] and one of the most prominent indicators of the presence of senescent cells in aged tissues [10]. One of the most common mediators of CS is the inhibition of Rb phosphorylation, which results in the inactivation of the E2F transcription factor and its target genes involved in cell cycle progression [11]. The activation of growth pathways, via the mammalian Target of Rapamycin (mTOR), and the autophagic response appear additional important players in establishing CS [12]. One of the major problems in research around CS is the characterization of senescent cells and the absence of a universal biomarker. Therefore, the best way to characterize senescent cells appears to consist in the use a pool of different biomarkers. In addition to activation of p16 and p53 pathways, other hallmarks that can be used to identify senescent cells include an altered morphology (i.e. increased size), activation of senescence-associated β-galactosidase (SA-β-Gal), emergence of chromatin aggregates (heterochromatin foci), markers for activated DNA damage and production of the SASP that include several proteins involved in the inflammation process [13]. However, recent observations support the hypothesis that senescence can be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify, much like tumorigenesis but without cell proliferation as a driver [3]. According to this point of view, senescent cells are roughly subdivided into two main classes (acute senescent cells and chronic or late senescent cells) based on their kinetic of induction and functionality. Acute senescent cells are formed from specific type of cells as a consequence of a biologic program useful for wound healing, tissue repair and embryonic development. Late senescent cells are formed from almost all type of cells (including post-mitotic cells such as neurons and cardiomyocytes) and seem to be not part of a biological program. This last example of CS develops after periods of progressive cellular stress or damage, such as the aging process. Studies of human tissues and cancer-prone mice argue strongly that CS is one of the most important processes to suppress cancer in vivo [4]. Nevertheless, the altered functional profile of senescent cells might alter tissue microenvironments in ways that can promote cancer in the surrounding
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