Targeting cellular senescence in cancer by plant secondary metabolites: A systematic review

https://doi.org/10.1016/j.phrs.2021.105961Get rights and content

Abstract

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.

Introduction

Senescence, one of the most critical concepts in biology, is defined as irreversible cellular growth arrest associated with morphologic changes including flattening, enlargement, enhanced granularity, and inhibition of telomerase activity. The first definition of the cellular senescence phenomenon was provided by Moorhead and Hayflick in 1960, following the observation of the limitation of human diploid fibroblast divisions even before stopping their growth [1], [2]. Inhibition of tumor suppressor genes and/or induction of mutant oncogenes begins with a sustained and powerful anti-proliferative process. This condition refers to oncogene-induced senescence (OIS), which triggers the senescence cascade by affecting the various signaling pathways involved in apoptosis, necrosis, inflammatory, and oxidative stress responses [3]. Senescent cells can lead to a progressive functional deterioration in age-related pathologies, including atherosclerosis and osteoarthritis, by interfering with the normal physiology of the tissues [1], [4]. Furthermore, it was reported that accumulation and number of senescent cells in the central nervous system can lead to the induction of neurodegenerative disease and aging, which may exert a remarkable role in exacerbating the severity of degenerative disorders or predisposing to neuronal-related disorders [5]. Furthermore, wound healing and embryogenesis are two reported physiological processes that point to senescence having beneficial roles in completing their processes and related associated mechanisms [6], [7].

Cellular senescence is an essential process that exerts a substantial role in cancer therapy and developing tumors. The occurrence of senescence in tumor cells can improve and enhance the therapeutic outcome of cancer treatment and is considered one of the new treatment options. On the other hand, it may also induce unintentional consequences in non-tumor cells by provoking secondary tumors, inflammation, and cancer relapse [1], [8], [9]. Induction of the senescence process, associated with facilitating immune cell infiltration and suppressing the cellular proliferation, leads to the tumor-suppressive and anticarcinogenic mechanism (autocrine response). Conversely, by facilitating the metastatic mechanisms and enhancing the proliferation of bystander cells, senescence acts as a carcinogen inducer and tumor-promoting factor in neighboring cells. These effects are termed paracrine effects [9]. These dual roles of tumor suppression and growth are a result of the secretion and expression of mediators, including growth factors, tissue remodeling factors, proteolytic enzymes, pro-inflammatory cytokines, and chemokines that could be involved in the variant signaling. Accordingly, senescence plays a key role in two manners of autocrine and paracrine effects, mediated by senescence-associated secretory phenotypes (SASPs) [10].

Plant secondary metabolites are compounds that possess various biological roles. Phenolic compound, alkaloids, terpenes/terpenoids, and sulfur-containing structures are more available classes of secondary metabolites with particular biological activities, including neuroprotective, anti-inflammatory, antimicrobial, antioxidant, and cardioprotective properties [11], [12], [13], [14], [15], [16], [17]. It was demonstrated that plant secondary metabolites exert significant roles in treating cancer and reducing several in vitro and in vivo tumorigenic and inflammatory factors [13]. The capability of plant secondary metabolites to influence suppression of paracrine signals and increase and amplify autocrine signals of cell senescence, seems to be an interesting, attractive, and impressive strategy for cancer prevention and treatment. Over the years, emerging evidence has highlighted the critical role of cell senescence in cancer [1], [18], [19]. In a recent review, polyphenols have been shown to be hopeful therapeutic agents in targeting special mediators involved in cellular senescence [20]. However, there is an urgent need to understand the exact dysregulated pathways of cell senescence, as well as the effects of phytochemicals in regulating senescence.

The present review intends to understand the therapeutic targets of phytochemicals as well as interconnected signaling pathways in senescence. This is the first systematic and comprehensive review that provides a hopeful antineoplastic perspective of plant secondary metabolites, as it focuses on cell senescence to investigate novel therapeutic compounds in the prevention and treatment of cancer.

Section snippets

Methodology of literature search

The current systematic and comprehensive review was conducted on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria. Accordingly, a systematic literature search was performed through electronic databases, including Scopus, Science Direct, PubMed, and Cochrane to cover English language articles until 30 April 2021. The systematic search in databases was carried applying the following keywords: “Senescence” AND (“malignancy” OR “cancer” OR “tumor” OR

The mechanistic insights behind cancer senescence: autocrine and paracrine

Senescence is a double-edged sword process during tumor growth/suppression [21]. On one hand, senescence employs antitumorigenic mechanisms to stop the initiation and progression of tumor cells. On the other hand, senescent cells release SASPs factors to develop tumorigenic conditions in neighboring cells, such termed the paracrine pathway. Hence, highlighting the precise autocrine and paracrine signaling pathways of cell senescence could pave the road for targeting major dysregulated pathways

Promising roles of plant secondary metabolites in the attenuation of cancer-associated cell senescence: mechanistic approaches

As previously mentioned, senescence possesses two scenarios on the secretion of intrinsic (autocrine) and extrinsic (paracrine) signaling mediator in cancer. Plant-derived natural products, with their significant roles in interfering with various therapeutic pathways, displayed the potential of targeting both the aforementioned senescent pathways.

Clinical regulation of senescence by phytochemicals: cancer and beyond

Targeting senescence is one of the main attractive strategies for the treatment of variant diseases, includes cancer. Accordingly, several clinical trials have been developed to investigate the effects of such a phenomenon on the progression and suppression of cancer [243], [244]. In this line, senescence shows undeniable roles in the progression/suppression of cancer in clinical studies. Chemotherapy-related treatments lead to cell death, often via inducing senescence/apoptosis, resulting in

Conclusion

In recent years, prevailing reports have been evaluating the role of cellular senescence in the progression or suppression of cancer. From the mechanistic point, SASPs have shown dual roles in the progression/suppression of cancer, which is termed paracrine/autocrine effects. While SASPs could prevent cancer progression in tumorigenic cells, they could trigger tumor conditions in neighboring cells. Phytochemicals have shown to be promising candidates in triggering senescence through the

Funding

Nothing to be declared.

CRediT authorship contribution statement

S.F.: Conceptualization, Software, Writing - original draft, Writing - review & editing. S.Z.M.: Writing - original draft, Writing - review & editing. A.A.R.: Writing - review & editing. A.B.: Conceptualization, Writing - original draft, Writing - review & editing, Project administration.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

Adobe Photoshop® software (version 2015, Adobe Inc., San Jose, CA) was used to draw mechanistic figures.

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