Hyperforin and Myrtucommulone Derivatives Act as Natural Modulators of Wnt/β-Catenin Signaling in HCT116 Colon Cancer Cells

Abstract

The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John’s wort (Hypericum perforatum L.) and myrtucommulone A (MC A) from myrtle (Myrtus communis) and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/β-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 μM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active β-catenin and β-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/β-catenin signaling in colon cancer.

The Role and Mechanism of Hyperoside against Depression-like Behavior in Mice via the NLRP1 Inflammasome

“…As shown in Figure 5C, including two pathways (p < 0.05), the C-type lectin receptor signaling pathway related to depression was identified. The results are consistent with the anti-inflammatory effects of HP and its main active components [31], its anti-metabolic disease [32], its anti-cancer [33], its neuroprotection [34], its anti-cardiovascular disease [35], and its signal transduction effects [36]. For example, TNF, TLR4, IL-2, BCL-2, etc., are closely related to inflammation, and these targets may be the key targets of Hyp, the main active component of HP, in the treatment of depression.…”

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

“…Independently of their mutations, all melanoma cell lines tested were very responsive to the damaging effects of HPF, as their viability was affected by EC50% HPF concentrations in the range of 2–4 µM ( Figure 1 ), lower than those previously registered in many other non-melanoma tumor cells [ 26 , 34 , 35 , 36 , 56 ]. Subsequently, we investigated the mechanism of HPF antimelanoma activity on the three BRAF-mutated cell lines.…”

“…HPF decreases bladder cancer cell survival, with EC50% of 10–20 µM, by increasing reactive oxygen species (ROS), calcium signaling and apoptosis and by blocking NF-κB activity [ 34 ]. Recently, cytotoxicity of HPF and its derivatives was discovered in colon cancer cells by a mechanism involving the Wnt/β-catenin signaling pathway [ 35 ]. Donà et al studied the HPF-elicited cytotoxicity in many human and murine cell lines [ 36 ].…”

Myrtucommulones and Related Acylphloroglucinols from Myrtaceae as a Promising Source of Multitarget SARS-CoV-2 Cycle Inhibitors

“…Moreover, their valuable therapeutic properties, such as antibacterial, antifungal, antiviral, antioxidant, anti-inflammatory, cytotoxic, and antiproliferative activities, have stimulated research efforts to identify bioactive compounds in their extracts. These extracts are known to be rich in terpenes, polyphenols, and other unique acylphloroglucinol compounds named myrtucommulones [ 2 , 16 , 17 , 18 ]. These phloroglucinol derivatives can be chemically divided into two main subclasses: oligomeric acylphloroglucinols and phloroglucinol–terpene adducts [ 2 ], with a very large structural diversity.…”