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By Gaetano Leto

The skeleton represents the third most common target for bone metastasis after the lungs and liver [1].  Many types of solid tumours, in particular, breast, prostate, thyroid, lung, and kidney cancer preferentially metastasize to bone [1,2]. The incidence of bone metastasis by tumour type, reaches 65–90% in prostate cancer (PCa), about 65–75% in breast cancer (BCa), 60% in thyroid cancer, 30–40% in lung cancer, 40% in bladder, cancer and, 20–25% in renal cell carcinoma, while it is less frequent in other malignancies such as melanoma (11–17%) and colorectal tumours (10%) [2,3]. The median-survival time after diagnosis of bone metastasis from  breast cancer, prostate cancer, thyroid cancer are 27 months, 25 months, and 23 months, respectively, while, in patients with renal, bladder, lung, and melanoma the  median survival is lower (12 months, 8 months, 7-9 months and 6 months respectively) [2-4]. Furthermore, in some haematological malignancies such as multiple myeloma the rate of incidence reaches 70–95% while, the current 2-year survival rate is 87.1% [4-6]. Despite the therapeutic advances registered in recent years, the systemic treatments for cancer-related bone disease based on the administration of anti-resorptive drugs and/or anti-tumour agents and/or radiopharmaceutical, is still facing several drawbacks. In fact, these therapeutic options are merely palliative, and has been shown not to have a significant positive impact on patients’ survival [7]. In addition, these agents may negatively affect normal bone metabolism with detrimental consequences for cancer patients [8]. Hence, the need to discover new compounds which can effectively thwart tumour cell growth while, at the same time, overcoming drug-induced bone loss and preserving bone health [9,10]. In this setting, numerous preclinical studies have been undertaken with the aim of discovering new molecules based on natural products from the plant environment [11]. The advantages of using natural products for therapeutic purposes, in particular in cancer treatment, are manifold as these substances appear, in general, to be i) readily available, ii) non-toxic to normal human cells, iii)may act as multi-target agents, since they may affect different signalling pathways that control cancer progression [11-13]. In this scenario, a consistent number of clinical and observational studies have provided evidence on the beneficial effects on human health of several bioactive compounds present in olive oil (OO) [14,15]. Olives and OO are important components in the Mediterranean diet (MD) [16,17]. Consumption of OO has been associated with a reduced risk of developing non communicable diseases (NCDs) including cardiovascular, metabolic, neurodegenerative, bone diseases and cancer [14,15,17-19]. The beneficial effects of OO on human health, have been mostly  attributed to the presence of numerous so-called “minor substances”, such as flavonoids, phenolic acids and alcohols, secoiridoids and lignans which are endowed with potent biological properties [14-19]. In particular, polyphenols such as Oleuropein, Hydroxytyrosol, and Oleocanthal have been shown to possess potent anti-inflammatory, antioxidant, antithrombotic, anti-microbial and anticancer properties [15,18-21] (Fig.1).

Fig.1 Chemical structure of olive oil polyphenols secoiridoids (oleuropein and oleocanthal) and phenolic alcohols (tyrosol and hydroxytyrosol) endowed with antioxidant, anti-inflammatory, neuroprotective, anticancer, and antimicrobial activity.

In this context, an increasing number of in vitro and in vivo studies have highlighted the fact that Oleuropein, the main bioactive phenolic compound present in olive leaves, the fruit and olive oil (and which is  also responsible  for bitter and pungent flavour of  OO), can hinder the growth and spread of  different types of human solid  tumours [15,20-22]. Preclinical investigations carried out in order to elucidate the specific mechanisms underlying these effects, have shown that this molecule interferes with some key steps in the malignant progression, namely tumour cell proliferation, survival, angiogenesis, invasion and dissemination of cancer cells to distant organs, by down-regulating the expression and activity of various growth factors, transcription factors, hormones, cytokines, chemokines and enzymes fostering these processes [11-13,15,20-25] (Fig 2).

Fig. 2 Effects of Oleuropein on cellular and molecular events promoting cancer progression. Oleuropein may inhibit the expression and activity of growth factors, hormones, proinflammatory cytokines, adhesion molecules and enzymes, which regulate different cellular processes involved in cancer progression, including i) cell proliferation and survival ii) epithelial-to-mesenchimaltransition (EMT) iii) cell migration and invasion, iv) angiogenesis, v) dissemination to distant organs and v)metastasis. Most of these signalling molecules result deregulated in several pathological conditions associated with bone loss and may also contribute to the formation of the so- called “bone pre-metastatic niche”.

Interestingly, increasing experimental evidence has demonstrated that, most of these molecules  appear to be involved  in the  formation of a permissive microenvironment, the so-called “(pre)metastatic niche”, which supports the homing, colonization and growth of  disseminated cancer cells in the bone and, eventually, their subsequent survival, dormancy and resistance to clinical treatments  [7,11-13,22,26] (Fig.2, Fig.3). Furthermore, recent reports have also highlighted the fact that these compounds appear to be involved in the regulation of bone turnover in normal conditions and in pathological processes associated with an excess of bone loss, such as inflammatory and autoimmune bone diseases, osteoporosis and cancer-related bone tumours [7,15,26,27] (Fig. 3).These findings are consistent with experimental and clinical observations showing  that the protective effects of Oleuropein on bone health are probably due to the ability of this compound to modulate the expression and activity of these factors the expression of which proves to be deregulated in various pathological conditions associated with altered bone remodelling processes [11,15,26,28-31].

Fig.3 Effects of Oleuropein on molecular signalling pathways linking chronic inflammation and bone colonization by cancer cells. Oleuropein exerts its anti-inflammatory effects by hindering the production of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) and by modulating the expression various signalling molecules, e.g., cytokines, chemokines, transcription factors and enzymes which, in physiological conditions, regulate the normal metabolic turnover of bone tissue while, their expression proves to be deregulated in various pathological conditions associated with bone loss such as chronic inflammatory processes and malignant bone disorders.

In this regard, recent in vitro studies have shown that Oleuropein can favour osteoblastogenesis by suppressing the expression of  the peroxisome proliferator–activated receptor γ (PPARγ), which functions as a transcriptional regulator of  adipocyte  differentiation and osteoblast inhibitor, while inhibiting osteoclastogenesis [32,33]. Ultimately, these findings support the concept for a potential clinical usefulness of Oleuropein in the prevention and treatment of cancer-related bone disease. These data also suggest that the administration of Oleuropein  in association with  antitumor drugs and/or bone modifying agents and/or radiopharmaceuticals might result in improved therapeutic activity, in the prevention of bone loss induced by these agents and in a decreasing probability of developing drug resistance by malignant cells [8-10,21,23]. Although, the results from preclinical in vitro studies are promising in this regard, unfortunately, there is still a lack of in vivo studies, with the specific aim of evaluating the therapeutic effectiveness of Ole on metastatic bone disease by using suitable experimental animal tumour models. Nevertheless, these observations prompt the need for extensive future experimental and clinical  investigations to assess the  impact of  Oleuropein on the  clinical management and outcome of patients with skeletal metastases and further confirm the beneficial effects of the various components of the MD in preventing the onset of severe chronic disease.

See more on this subject in:  Effects of oleuropein on tumor cell growth and bone remodelling: Potential clinical implications for the prevention and treatment of malignant bone diseases. Life Sci. 2020 Oct 30:118694. doi: 10.1016/j.lfs.2020.118694.

Prof. Gaetano Leto Education and Training

Correspondence:  gaetano.leto@unipa

Education

  • Degree cum laude in Biology, University of Palermo, Italy, (1977)
  • Post graduate Scholarship in Pharmacology and Toxicology c/o Institute of Pharmacology, Faculty of Medicine, University of Palermo, Italy, (1981)

Professional Experience

  • Laboratory Analysis c/o Navy Hospital, La Spezia, Italy (Military Service, 1978-79)
  • Visiting Scientist, Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, N.Y., USA (1985-87)
  • Affiliate Researcher, Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, N.Y., USA (1989)
  • Senior Researcher, Faculty of Medicine University of Palermo (2002)
  • Adjunct Professor of Pharmacology, Faculty of Medicine University of Palermo (2003)

Teaching Experience

  • 1991/1996: Toxicology c/o School for Health Care Professional, University Hospital, Palermo, Italy
  • 2003-2006; Cancer Chemotherapy c/o Faculty of Medicine, University of Palermo, Italy
  • 2002 to present: Pharmacology and Chemotherapy c/o School of Medicine, University of Palermo, Italy

Professional membership

  • American Association for Cancer Research (1996)
  • Metastasis Research Society (1992)
  • Italian Society of Pharmacology (2003)

Major research interest

  • Biochemical mechanisms of tumour invasion and metastasis with emphasis on the role of cysteine and metallo- proteinases and growth factors in bone metastasis formation
  • New potential circulating biomarkers of metastatic bone disease
  • New antimetastatic agents (in particular, studies on chemo-preventive and anti-metastatic activity plant-derived polyphenols).

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