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Migheli, R.;  Virdis, P.;  Galleri, G.;  Arru, C.;  Lostia, G.;  Coradduzza, D.;  Muroni, M.R.;  Pintore, G.;  Podda, L.;  Fozza, C.; et al. Antineoplastic Activities and Molecular Mechanisms of Inula viscosa. Encyclopedia. Available online: https://encyclopedia.pub/entry/32555 (accessed on 18 June 2024).
Migheli R,  Virdis P,  Galleri G,  Arru C,  Lostia G,  Coradduzza D, et al. Antineoplastic Activities and Molecular Mechanisms of Inula viscosa. Encyclopedia. Available at: https://encyclopedia.pub/entry/32555. Accessed June 18, 2024.
Migheli, Rossana, Patrizia Virdis, Grazia Galleri, Caterina Arru, Giada Lostia, Donatella Coradduzza, Maria Rosaria Muroni, Giorgio Pintore, Luigi Podda, Claudio Fozza, et al. "Antineoplastic Activities and Molecular Mechanisms of Inula viscosa" Encyclopedia, https://encyclopedia.pub/entry/32555 (accessed June 18, 2024).
Migheli, R.,  Virdis, P.,  Galleri, G.,  Arru, C.,  Lostia, G.,  Coradduzza, D.,  Muroni, M.R.,  Pintore, G.,  Podda, L.,  Fozza, C., & Miglio, M.R.D. (2022, November 02). Antineoplastic Activities and Molecular Mechanisms of Inula viscosa. In Encyclopedia. https://encyclopedia.pub/entry/32555
Migheli, Rossana, et al. "Antineoplastic Activities and Molecular Mechanisms of Inula viscosa." Encyclopedia. Web. 02 November, 2022.
Antineoplastic Activities and Molecular Mechanisms of Inula viscosa
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Cancer is a complex disease including approximately 200 different entities that can potentially affect all body tissues. Among the conventional treatments, radiotherapy and chemotherapy are most often applied to different types of cancers. Despite substantial advances in the development of innovative antineoplastic drugs, cancer remains one of the most significant causes of death, worldwide. The principal pitfall of successful cancer treatment is the intrinsic or acquired resistance to therapeutic agents. The development of more effective or synergistic therapeutic approaches to improve patient outcomes and minimize toxicity has become an urgent issue. Inula viscosa is widely distributed throughout Europe, Africa, and Asia. Used as a medicinal plant in different countries, I. viscosa has been characterized for its complex chemical composition in order to identify the bioactive compounds responsible for its biological activities, including anticancer effects.

Inula viscosa tomentosin inuviscolide intrinsic pathway of apoptosis

1. Introduction

Traditional herbal medicines are excellent sources of natural biologically active products with powerful therapeutic effects that can be utilized in the treatment of various diseases, including cancer. Inula viscosa (L.) Aiton. (Dittrichia viscosa L.) is a medicinal perennial plant belonging to the genus Inula and family Asteraceae and is considered one of the most crucial pharmaceutical plants in the Mediterranean Basin [1]. As a medicinal plant in, I. viscosa has been characterized in different countries for its complex chemical composition to identify the bioactive compounds responsible for its biological activities [2]. I. viscosa has long been used in folk medicine owing to its anti-inflammatory [3], anthelmintic, antipyretic, antiseptic, and antiphlogistic activities [4][5], and in the treatment of lung disorders [6] and diabetes [7]. Hernandez et al. isolated and tested several flavanones, such as sakuranetin, 7-O-methylaromadendrin, and 3-acetyl-7-O-methylaromadendrin showing relevant effects on enzymes involved in the inflammatory response [8]. Recently, several studies have explained the biological mechanisms triggering the anti-inflammatory effect of I. viscosa, which are based on the inhibition of COX1, COX2, and iNOS enzymatic activity [9][10]. Kheyar-Kraouche et al. performed a high-performance liquid chromatography associated with electrospray ionization mass spectrometry on the ethanolic extract obtained by I. viscosa leaves growing in Algeria. They identified different phytochemical components, including phenolic acids, flavonoids, lignans, and terpenoids; some of which were recognized for the first time and belong to different subfamilies of compounds [11].
Recently, cytotoxic and anticancer activities of I. viscosa have been demonstrated in various cancer cell lines [12][13][14]. Therefore, elucidating the anticancer properties of this plant could be a relevant strategy to identify new antitumor agents. Different biologically active compounds belonging to several families isolated from I. viscosa were tested alone or in association with cancer cell lines [15][16][17][18], and in vivo experiments showed their strong antineoplastic activity [19][20]. Messaoudi et al. performed a chemical composition analysis of different I. viscosa extracts from three different regions of Morocco, revealing the presence of sesquiterpene lactones (SLs), tomentosin, and inuviscolide as major representative compounds, with tomentosin concentrations ranging from 22% to 64% and inuviscolide concentrations ranging from 0% to 58% in different Moroccan regions [14]. The SL structure consists of 15-carbon terpenoids obtained by the condensation of three isoprene units and a lactone ring [21]. Most sesquiterpenes, but not all, contain the α-methylene-γ-butyrolactone motif, the functional group responsible for their biological effects, and, above all, the antitumor activity [22]. Although they are mainly found in the Asteraceae family, SLs have been identified in several families of flowering plants, including Solanaceae, Araceae, and Cactaceae [23]. As reported by Wang et al., 396 types of sesquiterpenoids with high structural diversity have been isolated and characterized with the Inula (Asteraceae) genus [2].

2. Inula viscosa: Antineoplastic Activities and Molecular Mechanisms

Cytotoxic screening models represent crucial preliminary data for analyzing the antineoplastic properties of selected plant extracts. Early tests were cell-based assays performed on established cell lines in which the toxic effects of plant extracts or isolated compounds could be measured. Conventional antitumor agents display significant cytotoxic activities in cell culture systems [24].
Benbacer et al., with the purpose of developing new anticancer drugs against cervical cancer, applied the human cervical carcinoma SiHa and HeLa cell lines as a model system to screen the anticancer effects of plants from traditional Moroccan medicine. In particular, they demonstrated that I. viscosa hexane extract showed pronounced cytotoxic effects against both cervical cancer cell lines, inducing dose-dependent cell growth inhibition by stimulating apoptosis, which is related to the decrease in mitochondrial membrane potential (ΔΨm) and increase in intracellular reactive oxygen species (ROS) production. Thus, I. viscosa extracts showed significant cytotoxic effects against cervical cancer cell lines through the inhibition of proliferation and induction of apoptosis involving a mitochondria-mediated signaling pathway by pro-caspase activation, BCL-2 expression, and PARP cleavage [13]. The same group demonstrated that I. viscosa extracts target the telomerase machinery and induce apoptosis in human cervical carcinoma cell lines (SiHa and HeLa) and that the molecular mechanism underlying I. viscosa extract-induced apoptosis includes a caspase-3 mediated signaling pathway [25].
An interesting study by Messaoudi et al. showed the cytotoxic activity of ethyl acetate and ethanolic I. viscosa extracts harvested from three different regions of Morocco (Taouante, Sefrou, and Imouzzer) in two breast cancer cell lines, MCF7, an estrogen receptor-positive cell line, and MDAMB-231, an estrogen receptor-negative cell line. These two I. viscosa extracts showed different toxicity on breast cancer cells, suggesting that the different cytotoxic activity can be an integral effect of the combination of three major compounds, tomentosin, inuviscolide, and isocostic acid which are present in variable concentrations in plants from different regions. Furthermore, the reduced toxicity exerted by the two extracts on MCF-7 cells when compared with MDA-MB-231 cells suggests that heterogeneous susceptibility could be dependent on the activation of different signaling pathways [14]. In addition, they demonstrated that ethanolic and ethyl acetate extracts of I. viscosa from Taounate, Imouzzer, and Sefrou had different rates of polyphenols associated with different antioxidant activities [26]. Further studies have demonstrated the selective cytotoxic effects of I. viscosa on MCF-7 cells [27][28].
Bar-Shalom et al. examined the possible therapeutic effects of I. viscosa aqueous extract on colon cancer cell growth in vitro and tumor growth in vivo, using a xenograft mouse model. In vitro experiments revealed that exposure of colorectal cancer cells to I. viscosa extract significantly reduced cell viability in a dose- and time-dependent manner. Interestingly, the analysis of the molecular mechanisms underlying the I. viscosa effect showed the activation of caspase-9 in HCT116 well-differentiated cells and of caspases-8 and -9 in colo320 poorly-differentiated cells. These findings suggest that I. viscosa extract induces apoptosis through the intrinsic mitochondrial pathway in well-differentiated cells, and through both the intrinsic and extrinsic pathways in poorly-differentiated cells. In vivo studies revealed that treatment with I. viscosa extract inhibited tumor growth in mice transplanted with MC38 cells, showing a strong reduction in the weight and volume of neoplastic lesions. Interestingly, no side effects such as weight loss, behavioral changes, ruffled fur, or changes in kidney and liver function were observed, suggesting the absence of toxicity from I. viscosa [29].
I. viscosa collected from an uncontaminated area of the National Park on Asinara Island, Sardinia, revealed powerful anti-lymphoma activity. Specifically, Raji cells treated with increasing concentrations of I. viscosa ethanolic extract demonstrated a dose- and time-dependent decrease in cell viability, displaying a reduction in cell proliferation obtained by the induction of cell cycle arrest in the G2/M phase, and a dose-dependent increase in cell apoptosis. A gene expression analysis of signal transduction and apoptotic pathway players involved in B-lymphocyte functions showed that the molecular mechanisms involved in I. viscosa anticancer activity were characterized by the downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1), as well as in the inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A) [30].
An interesting study evaluated the cytotoxic and anticancer effects of I. viscosa methanol and aqueous extracts on the malignant melanoma cell lines A2058 and MeWo, and normal fibroblasts. Cytotoxicity, apoptosis induction, and migration suppression were strongly induced in malignant melanoma cell lines by I. viscosa methanol extracts compared to the aqueous extracts [31], confirming that the solvent used in the extraction steps can influence the content and biological activity of the extract [25][27]. For the first time, an epigenetic mechanism underlying the anticancer activity of I. viscosa has been demonstrated. Specifically, I. viscosa methanol extract promotes the downregulation of miRNAs related to epithelial-mesenchymal transition and poor prognosis in malignant melanoma, such as miR-191 and miR-193, while favoring the overexpression of miR-579 and miR-524, which mainly repress the MAPK signaling pathway in malignant melanoma [31].
The ubiquitin–proteasome system plays a key role in intracellular proteolysis, particularly in the degradation of abnormal proteins. In fact, it is directly involved in the regulation of most biological processes, such as cell cycle, apoptosis, muscle differentiation, and immune response [32]. Many studies have revealed that proteasome levels can be used as biomarkers for various types of cancer [33][34][35]. Recently, Yaagoubi et al. investigated the antitumor effects and proteasome inhibition capacity of I. viscosa extract in a mouse model of DMBA/croton oil-induced skin carcinoma. Animals received treatment with the extract before and after the induction of skin carcinogenesis, showing that I. viscosa extract inhibited the development of papilloma in mice. Furthermore, ingestion of I. viscosa extract delayed the formation of cutaneous papillomas in animals and simultaneously decreased the size and number of papillomas. A structure–activity study showed that I. viscosa extract contains bioactive molecules with much greater inhibition of the subunits of the proteasome, as well as a decrease in the concentration of proteasome and its catalytic activity in serum and intracellularly when compared to chemically synthesized inhibitors, thus emerging as a new candidate for targeted therapy against skin carcinoma. Specifically, molecular docking analysis revealed that tomentosin, inuviscolide and isocostic acid compounds obtained from I. viscosa extract were stabilized in the pocket of the 20S proteasome β5 receptor subunits by various interactions, mirroring the same mechanisms exerted by carfilzomib, a potent second-generation proteasome inhibitor with significant anti-myeloma activity [36]. I. viscosa extracts also increased cell cycle arrest and cell death in the glioblastoma LN229 cell line, characterized by a TP53 mutation, compared to U87MG cells with wild-type TP53. SW620 cells were more sensitive to I. viscosa extracts, suggesting that they may contain molecules with high therapeutic potential against MDR cell lines. PC-3 are androgen-insensitive and apoptosis-resistant prostate cancer cells, on which I. viscosa extracts induce growth inhibition, cell cycle arrest and apoptosis, supporting the idea that active compounds effectively targeting extrinsic and intrinsic apoptosis pathways are present in the plant [37]. Table 1 summarizes the biological and molecular effects induced by I. viscosa treatment with in vitro and in vivo models.
Table 1. Summary of biological and molecular effects induced by Inula viscosa treatment with in vitro and in vivo system models.

References

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