Crithmum maritimum Improves Sorafenib Sensitivity by Decreasing Lactic Acid Fermentation and Inducing a Pro-Hepatocyte Marker Profile in Hepatocellular Carcinoma.

Edible plants are gaining importance as an integrative therapy for many chronic diseases, including cancer. We first reported that the edible wild plant Crithmum maritimum L. inhibits the growth of hepatocellular carcinoma (HCC) cells by exerting a multitarget action on cellular metabolism and bioenergetic profile. Here, we show that Crithmum maritimum ethyl acetate extract significantly increases the responsiveness of HCC cells to the chemotherapeutic drug sorafenib by reducing lactic acid fermentation and inducing a pro-hepatocyte biomarker profile. Our findings strengthen the role of Crithmum maritimum L. as a valuable nutraceutical tool to support pharmacological therapeutic interventions in HCC.

The Edible Plant Crithmum maritimum Shows Nutraceutical Properties by Targeting Energy Metabolism in Hepatic Cancer.

In the past few years, evidence has supported the role of plants as a valuable tool for the development of promising therapeutic support options for many diseases, including cancer. We recently discovered that the edible wild plant Crithmum maritimum L. effectively inhibits the growth of hepatocellular carcinoma (HCC) cells and we provide insights into the biological mechanisms involved. Here, we aimed to characterize the effect of ethyl acetate extract of Crithmum maritimum on the bioenergetic phenotype of HCC cells and if this is associated with the anti-tumour effect we previously described. Results show that Crithmum maritimum significantly increases cellular respiration and reduces lactic fermentation in HCC cells, and that this reduction of the fermentative glycolytic phenotype is linked to inhibition of HCC growth. These data provide new preclinical evidence supporting the role of Crithmum maritimum L. as a nutraceutical option to expand the therapeutic opportunities in the management of HCC.

Treatment of liver cancer cells with ethyl acetate extract of Crithmum maritimum permits reducing sorafenib dose and toxicity maintaining its efficacy.

OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most frequent tumours worldwide and available drugs are inadequate for therapeutic results and tolerability. Hence, novel effective therapeutic tools with fewer side effects are of paramount importance. We have previously shown that Crithmum maritimum ethyl acetate extract exerts a cytostatic effect in HCC cells. Here, we tested whether C. maritimum ethyl acetate extract in combination with half sorafenib IC50 dose ameliorated efficacy and toxicity of sorafenib in inhibiting liver cancer cell growth. Moreover, we investigated the mechanisms involved. METHODS: Two HCC cell lines (Huh7 and HepG2) were treated with C. maritimum ethyl acetate extract and half IC50 sorafenib dose usually employed in vitro. Then, cell proliferation, growth kinetics and cell toxicity were analysed together with an investigation of the cellular mechanisms involved, focusing on cell cycle regulation and apoptosis. KEY FINDINGS: Results show that combined treatment with C. maritimum ethyl acetate extract and half IC50 sorafenib dose decreased cell proliferation comparably to full-dose sorafenib without increasing cell toxicity as confirmed by the effect on cell cycle regulation and apoptosis. CONCLUSIONS: These results provide scientific support for the possibility of an effective integrative therapeutic approach for HCC with fewer side effects on patients.

1H-NMR metabolomics reveals a multitarget action of Crithmum maritimum ethyl acetate extract in inhibiting hepatocellular carcinoma cell growth.

Hepatocellular carcinoma (HCC) is nowadays the sixth cause of tumour-related deceases worldwide, estimated to become the third in Western countries by 2030. New drugs for HCC treatment still have many adverse effects. Several lines of evidence indicate that plant metabolites offer concrete opportunities for developing new therapeutic strategies for many diseases, including cancer. We previously reported that ethyl acetate extract of a spontaneous edible plant harvested in Apulia, Crithmum maritimum, significantly inhibited cell growth in HCC cells. By 1H-NMR spectroscopy, here we show that Crithmum maritimum ethyl acetate extract counteracts the Warburg effect, by reducing intracellular lactate, inhibits protein anabolism, by decreasing amino acid level, and affects membrane biosynthesis by lowering choline and phosphocholine. Also, we observed an effect on lipid homeostasis, with a reduction in triglycerides, cholesterol, monounsaturated fatty acids (MUFA), and diunsaturated fatty acids (DUFA), and an increase in polyunsaturated fatty acids (PUFA). Taken together, these data demonstrate that Crithmum maritimum-induced cytostasis is exerted through a multi-effect action, targeting key metabolic processes in HCC cells. Overall, our findings highlight the role of Crithmum maritimum as a promising tool for the prevention and the improvement of the therapeutic options for HCC and other types of tumours.

Inhibition of Hepatocellular Carcinoma Growth by Ethyl Acetate Extracts of Apulian Brassica oleracea L. and Crithmum maritimum L.

Nowadays, a growing body of evidence supports the view that plants offer an extraordinary opportunity to discover and develop new promising therapeutic strategies for many diseases, including cancer. Here we tested the anticancer action against Hepatocellular carcinoma (HCC) of extracts obtained from two plants harvested in Apulia, namely Brassica oleracea L. and Crithmum maritimum L. B. oleracea was grown in biodynamical agriculture without any agrochemical input, instead C. maritimum was collected on Apulian coasts and is still commonly eaten in Apulia. HCC, one of the most frequent tumors worldwide, is estimated to become the third leading cause of cancer-related deaths in Western Countries by 2030. The approved synthetic drugs for the treatment of HCC are currently inadequate in terms of therapeutic results and tolerability. Hence, aim of the present study was to test the anticancer action against HCC of extracts obtained from Brassica oleracea L. and Crithmum maritimum L. We preliminary prepared extracts from both plants using four solvents with different polarity: hexane, ethyl acetate, methanol and ethanol. Then, we tested the effect of the different fractions in inhibiting HCC cell growth. Finally, we characterized the mechanism of action of the most effective fraction. We found that ethyl acetate fractions from both plants were the most effective in inhibiting HCC growth. In particular, we demonstrated that these fractions effectively reduce HCC growth by exerting, on one hand, a cytostatic effect through their action on the cell cycle, and on the other hand by triggering apoptosis and necrosis. Our findings support the notion that ethyl acetate fractions from Apulian B. oleracea and C. maritimum can be in perspective considered as promising tools to expand the opportunities to identify new and not toxic anticancer therapeutic approaches for HCC. Further pharmacological investigations will shed light on how this could be effectively achieved. Graphical Abstract Experimental workflow for the detection of the ethyl acetate extract of Brassica oleracea L. and Crithmum maritimum L. as an active fraction in inhibiting HCC cell growth.