Novel plant-derived target drugs: a step forward from licorice?

Abstract

Isoliquiritigenin (ISL) is a chalcone compound with valuable pharmacological properties such as antioxidant, anti-inflammatory, anticancer and anti-allergic activities. With regard to anticancer property, ISL was able to suppress HIF-1α level, VEGF expression and secretion, cell migration and to decrease the expression and secretion of MMP-9/-2. These effects may be mediated through inhibition of p38, PI3K/Akt and NF-κB signaling pathways. Thus, low concentration of ISL may have therapeutic potential in the treatment of aggressive breast carcinoma and other neoplasms.

Keywords::

• breast cancer
• chalcone
• isoliquritrigenin
• MCF-7

The first suggestion that isoliquiritigenin (ISL) may have antiproliferative effect goes back to 1991 when Yamamoto et al. [1] demonstrated that a topical application of a chalcone derivative, 4,2′,4′-trihydroxychalcone (ISL) inhibited epidermal ornithine decarboxylase (ODC) induction and ear edema formation, that is, inflammation, caused by a topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in CD-1 mice. In addition, they found that ISL potently inhibited 7,12-dimethylbenz[alpha]anthracene (DMBA)-initiated and TPA-promoted skin papilloma formation. This inhibitory effect of ISL was not due to any damage inflicted on the initiated cells, but due to its antitumor-promoting action. ISL also inhibited epidermal ODC induction and skin tumor promotion caused by 7-bromomethylbenz[alpha]anthracene (BrMBA), a non-TPA type of tumor-promoting agent, in DMBA-initiated mice. Conversely, ISL inhibited neither 12-lipoxygenase nor cyclooxygenase (COX) in epidermal subcellular fractions. This compound, however, inhibited TPA-stimulated prostaglandin E2 (PGE2) production in intact epidermal cells. ODC induction caused by TPA was inhibited by a topical application of a COX inhibitor as indomethacin. The inhibition of ODC induction by indomethacin was counteracted by a topical application of PGE2, while inhibition caused by ISL was not overcome by PGE2. These results suggested that a mechanism other than the inhibition of PGE2 production was involved in the antitumor-promoting action of ISL. Moreover, ISL failed to inhibit phospholipase A2 activity of platelet sonicates, but inhibited platelet 12-lipoxygenase and 5-lipoxygenase in polymorphonuclear leukocytes. Therefore, it might be possible that ISL exerts its antitumor-promoting action through the lipoxygenase inhibition by acting on cells other than the target epidermal cells.

Subsequently, a number of studies have suggested that ISL was able to significantly inhibit the proliferation of cancer cell lines. In particular, in prostate cancer cell lines ISL acts in a dose-dependent and time-dependent manner [2] through the inhibition of c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling which may be one of the mechanisms by which ISL inhibits cancer cell invasion and migration [3]. ISL inhibited basal and EGF-induced cell migration, invasion and adhesion dose dependently. It decreased EGF-induced secretion of urokinase-type plasminogen activator (uPA), matrix metallopeptidase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and VEGF, but increased TIMP-2 secretion in a concentration-dependent manner. It also decreased the protein levels of integrin-α2, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) [3]. ISL demonstrated to be able to cause growth inhibition and facilitate apoptosis in colon cancer cells, inducing phase-specific cell cycle arrest in G2 [4]. More recently, the antiproliferative effect of ISL was documented by inhibition of both TNF-α-induced nuclear factor-kappaB (NF-κB) activity and total HDAC (histone deacetylase) activity of classes I, II and IV [5]. Also in multiple myeloma (MM) cell lines, ISL was effective in inhibiting cell growth via blocking IL-6 signaling, suggesting that it might serve as a promising therapeutic agent for treatment of MM [6].

With regard to breast cancer cell lines, ISL was found to exhibit estrogenic effect in vitro, in MCF-7 breast cancer cells, with a cytotoxic action, at higher levels, also in HeLa cells which are steroid negative [7]. Recently, ISL showed to be an inhibitor of aromatase enzyme activity in vitro [8]. Moreover, this compound was able to block MCF-7aro cells (MCF-7 cells stably transfected with CYP19) growth, and when added in diet, significantly inhibited the xenograft growth in ovariectomized athymic mice transplanted with MCF-7aro cells [8]. ISL also inhibited aromatase mRNA expression and suppressed the activity of CYP19 promoters I.3 and II in MCF-7 cells [8]. In addition ISL, which is known to be a potential suppressor of COX-2, in a recent study, demonstrated to significantly inhibit phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in non-tumorigenic MCF-10A breast cell line, by modulating extracellular signal-regulated kinases (ERK)-1/2 signaling, suggesting disease prevention properties of licorice [9].

The Wang et al. study [10] investigated on the effect of ISL on the growth of human breast carcinoma cells to determine whether ISL was toxic or inhibitory to the breast cancer cells. MCF-7 cells and MDA-MB-231 were chosen as experimental models. In these cell lines, ISL suppressed hypoxia-inducible factor (HIF)-1α level, VEGF expression and secretion (not in MCF-7), cell migration and decreased the expression and secretion of MMP-9/-2. The authors claim that these effects may be mediated through inhibition of p38, PI3K/Akt and NF-κB signaling, and sustain their hypothesis with a number of well-designed laboratory experiments.

Expert opinion

Although consumption of fruits, vegetables, spices and cereals has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood.

In fact, the chalcones contained in the above-mentioned natural products have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, anti-oxidant, anticancer and antidiabetic activities. However, the mechanism of action of these compounds in inflammation that controls both the immune system and tumorigenesis has been rarely explained. A few chalcones derived from natural sources have been shown to inhibit tumor cell invasion and metastasis by targeting one or more molecules as NF-κB, TNF-α, VEGF, ICAM-1, VCAM-1, bcl-2, MMP, etc. Among these chalcones, ISL seems to be one of the most active [5].

In fact, this paper [10] suggests that low concentration of ISL may have therapeutic potential in the treatment of aggressive breast carcinoma by inhibiting p38, PI3K/Akt and NF-κB signaling, resulting in the inhibition of expression of VEGF, HIF-1α, MMP-9 and MMP-2. All these suppressions caused by ISL are possibly involved in the antiproliferative effect observed in breast cancer cell lines through reduction of the migration of MDA-MB-231 and MCF-7. For these reasons, ISL is to be considered a very promising antiproliferative agent for its capacity to interfere with multiple pathways. However, a number of questions remain open before ISL and other similar products will be introduced in clinical practice: i) Are the effects observed in vitro reproducible in vivo? ii) What about the therapeutic activity of ISL in primates and in humans? iii) Which are the doses to be used in vivo and, in particular, in clinical Phase I – II studies? iv) Will these doses have inhibitory effect on cancer without causing intolerable toxic effect to the host? v) How long will we expect for clinical trials on ISL?

In conclusion, ISL is a very interesting natural product and we wish a bright future to it, however more investigations are needed before qualifying it as an antineoplastic agent.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.