Mini Review / Open Access

DOI: 10.31488/jjm.1000138

Tumor Liberated Protein (TLP) as Potential Target for Immunotherapy Associated to Nutraceutical Supplements

Matteo Micucci1, Giulio Tarro*2,3

  1. Pharmacy and Biotechnology Department -Alma Mater Studiorum University of Bologna

  2. Foundation T. & L. de Beaumont Bonelli for cancer research, Naples, Italy

  3. Committee on Biotechnologies and VirusSphere, world Academy of Biomedical Technologies, UNIESCO, Paris, France

*Corresponding author:Giulio Tarro, Via Posillipo 286, 80123 Naples, Italy

Abstract

The concept that the immune system can recognize and control tumor growth can be traced back to 1893 when William Coley used live bacteria as an immune stimulant to treat cancer, but the enthusiasm for cancer immunotherapy has been moderate due to limited clinical efficacy. This limited efficacy is due to the ability of tumor cells to avoid recognition and elimination by the immune system, allowing them to become established in the host (1). Over the past few decades, tremendous progress has been made in theunderstanding of how cancer evades the immune system, which in turn offers new ways to stop cancer immune evasion in favor of eliminating cancer cells.

TLP complexes (proteins released from tumors) show antigenic activity that may be applied for diagnostic aims and represent a target for immunotherapy. TLP antigens are proteins found in many cells, and one of the main components was first isolated from lung cancer tissues [1]. From this protein, it was obtained an epitope on whose basis it was possible to develope a rabbit anti-TLP serum [2].In fact, the antibodies devolpedagainst these antigens are able to mark lung carcinoma tissues and to recognize the specific sequences previously found in TLP [1]. In addition, TLP was found in sera from patients with lung and colorectal cancer, in lung and colorectal cancer tissues and cell lines [2]and detected in DHD-K12 cell line in vitro and in vivo,in metastases induced by DHD-K12 cell injection in rats [3]. Furthermore, TLP exerts specific mitogenic activity as its intradermic inoculation results in lymphocyte blastogenesis [4].

TLP can be detected in human sera using an ELISA assay. It is worthy of note the possibility to apply a kit able to measure sera TLP values as diagnostic tool for lung cancer. Infact, the identification of TLP in sera from healthy subjects may result in an early diagnosis, thus providing the possibility to exert preventive strategies including, among others, the intervention through the modification of life styles, and the consumption of nutraceutical supplements that may contrast the molecular mechanisms underlying the onset and the progression of lung cancer.

We are thinking to to different ways to develop preventive strategies:

  • vaccine

  • life style

These 2 ways are not in contrast between them, but they should be done together.Infact, there is a plethora of phytocomplexes able to produce molecular mechanisms.Camellia sinensisconsumption seems to exert preventive role on carcinogenesis. These activities are, atleast in part, due to the severals effects of (−) epigallocatechingallate (EGCG). The mechanisms underlying the chemopreventive effects concern the affetcion of carcinogen-metabolizing enzymes, of cell-signaling pathways apoptosis induction, arrest of cell-cycle, transcription factors activation inhibition.

EGCG (1–40 μM) reduces human lungcancer cells proliferation upregulating p53 expression, resulting from the augment of p53 phosphorylation at Ser15and Ser20 and the induction of its transcriptional activity [5].Another protein involved in EGCG chemiopreventive activity is HIFα [6].

Furthermore, EGCG shows cytotoxicity against drug-sensitive and drug-resistant SCLC cellsIn both cell lines, DNA fragmentation and S-phasecell-cycle arrest were observed [7].In particular this flavonoid was shown to inhibit cell proliferation in in erlotinib-sensitive and resistant cell lines, in addition to producing the same effect in H460 xenografts [8].

Green tea, EGCG and GTP exert preventive and therapeutic activities towards lung cancer in animals. Infact the oral administration of EGCG to nude mice augmented H1299 cells apoptosis through several mechanisms including the induction of oxidative DNA damage [9]. Theaflavin and EGCG inhibit proliferation at different stages of experimental lung carcinogenesis in the mouse model of benzo(a)pyrene [B(a)P]-induced lung carcinogenesis [10]. Furthermore, the administration of GTP and black tea polyphenols to Swiss albino mice decreased the incidence of lungs diethylnitrosoamineinducedalveologenictumors, as result of Akt expression, cox and nuclear factor kappa-B (NF-κB) inhibition [11].

Pomegranate (PunicagranatumL., Punicaceae), is an edible fruit whose juices and extracts are rich in hydrolizable tannins such as punicalagin and punicalin. A pomegranate fruit extract (PFE) reduced cell-viability of human lung cancer A549 cells without affecting normal human bronchial epithelial cells. In particular, this vegetal extract, in A549 cells, produced cells arrest in G0–G1 phase and reduced the expressions of cyclins, cyclin-dependent kinases. The molecular mechanisms underlying this activity include the inhibition of MAPK, PI3K, phosphorylation of Akt, NF-κB and markers of cell-proliferation [12].

In the same work, it has been observed that PFE oral administration to nude mice with implanted with human lung cancer A549 cells resulted in a reduction of tumor growth, and delayed solid tumors formation. Also in the experimental models of lung cancer induced by B(a)P and N-nitroso-tris-chloroethylurea (NTCU), PFE oral administration inhibited cancer growth and progression, and angiogenesis, through several mechanisms including NF-κB, MAPK, PI3K,Akt phosphorylation inhibition [13].

Other plants extract able to inhibit cancer cells proliferation are those obrained by Urticadioica L.,[14] Artemisia annua,[15] among others. In addition, for several plants, such as HedyotisdiffusaWilld., the direct anticancer effect occuring through several mechanisms in associated to the ability to activate immunity [16]. Also several flavonoids, such as, vitexin, nobiletin were shown to inhibit lung cancer cells proliferation affecting a plethora of molecolar networks [17, 18]. The same observation may be exerted for many other classes on natural compounds such asstilbens including resveratrol and piceatannol, ellagitannins such as geraniin, Sanguiin H6,Oenothein B,phytosterols such as beta sitosterol, daucosterolwhitaferin A [20-25].

In conclusion, the investigation of the anticancer activities of several plants extracts has provided some evidence for the potential clinical application. Many vegetal extracts and natural compounds act as anticancer agents exerting a cytotoxic effect against some cancer cells and increasing host immunity, potentially increasing organism ability to fight cancer [26].

Conflict of Interest Statement

The authors declares no conflict of interest

Acknowledgments

The authors thank for their support: Foundation T&L de Beaumont Bonelli for Cancer Research Napoli, Italy.

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Received: February 04, 2019;
Accepted: February 27, 2019;
Published: March 04, 2019.

To cite this article : Micucci M, Tarro G. Tumor Liberated Protein (TLP) as Potential Target for Immunotherapy Associated to Nutraceutical Supplements. Japan Journal of Medicine. 2019: 2:2.

©Micucci M, et al. 2019.