Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

Abstract

Glioblastoma is the most aggressive brain tumor with poor overall survival bellow 2 years. The natural compounds with anti-cancer properties, are thus gaining attention for possible adjuvant GBM treatment. In various cancer models Enterolobium contortisiliquum Trypsin Inhibitor (EcTI) proved to have anti-cancer effects. Here, we investigated the EcTI effects on GBM U87 cells and on mesenchymal stem cells (MSC) compared to their direct coculture (MSC/U87). MSC are present in tumor stroma, modulating GBM cells phenotype, and also represent potential drug delivery vehicle due to their tumor tropism. We showed that in p53-wild type U87 cells, metabolic activity was less affected by EcTI as in MSC monocuture, but the metabolic rate of mixed coculture was significantly reduced at lower EcTI concentration. Under coculture condition, EcTI potentiated MSC induced cell cycle arrest, possible due to highly increased p53, p21 and lower D1 expression, but there was no effect on apoptosis. Accordingly, in the coculture EcTI also enhanced Ca2+ signalling mediated via bradykinin receptor 2, being associated with nitric oxide release that highly impaired proliferation and invasion. The mechanism did not seem to involve changes in cell adhesion but rather it down-regulated the β1 integrin signaling with associated p-FAK in U87 cells, both supporting inhibition of invasion. Finally, some cytokines were down-regulated, indicating that EcTI inhibition of signalling might be mediated by cytokines. In conclusion, these results indicate that in cocultured MSC/U87 cells EcTI impairs the metabolic activity, proliferation, and reduced invasion, possibly associated with observed cytokines secretion. In this context, we confirmed that the plant derived protein potentiated the anticancer effects, induced by MSC, as represented by GBM U87 cell line.

A Bifunctional Molecule with Lectin and Protease Inhibitor Activities Isolated from Crataeva tapia Bark Significantly Affects Cocultures of Mesenchymal Stem Cells and Glioblastoma Cells

“…The decrease of total cell viability, as shown in Figure 1A, in cocultured cells at 24 h is thus due to dying MSCs, as these cells were more vulnerable to the apoptotic effect of the inhibitor, as one would expect (Figure 1B). Interestingly, these results are in contrast to our previous experiments with another protease inhibitor (EcTI), isolated from Enterolobium contortisiliquum , also of the same Kunitz-type family, but having no lectin-binding properties [30]. EcTI did not cause U87 cell death, neither in mono, nor in coculture, suggesting that the proteolysis inhibition per se does not play a role in apoptosis.…”

“…In this study, the adhesion of MSC and U87 cells alone to three ECM-related substrates remained unaltered upon CrataBL treatment, but was inhibited in U87 coculture pretreatment, especially with laminin, where the adhesion was significantly decreased at a higher (100 μM) CrataBL concentrations. CrataBL more effectively decreased U87 cell adhesion compared to the other Kunitz-type inhibitor, EcTI, which only slightly decreased the adhesion of U87 cells to fibronectin and MSC cocultured U87 cells to collagen IV [30]. CrataBL seems to interact in a more complex manner with cells to impair their adhesion to extracellular matrix components than EcTI.…”

Differences in the Inhibitory Specificity Distinguish the Efficacy of Plant Protease Inhibitors on Mouse Fibrosarcoma

“…In particular, inhibitors derived from Bauhinia bauhinioides , BbKI (human plasma kallikrein inhibitor) and BbCI (cruzipain inhibitor), were investigated in models of inflammation and reperfusion [ 10 , 17 ], venous and arterial thrombosis of mice [ 13 ], a prostate cancer model [ 18 ], cell invasion and angiogenesis in different cell lines [ 12 ], a pulmonary emphysema model in mice [ 14 ], and as a potential insecticidal agent [ 19 ]. EcTl, a trypsin inhibitor derived from Enterolobium contortisiliquum , was investigated in gastric cancer [ 11 ], triple-negative breast cancer [ 20 ], glioblastoma [ 21 , 22 ], the reduction of inflammation and pulmonary remodeling in induced lung inflammation [ 23 ], and in an asthma model [ 24 ]. In addition, EcTI was investigated in non-tumorigenic cells such as human mesenchymal cells [ 25 ] and showed no effects, demonstrating the potential use of these compounds as therapeutic targets.…”

Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

“…Particularly, some bacteria can convert amino acids in nitrosamines and induce DNA alkanisation and mutations (Kim, Lee, Jung, & Kim, 2017; Ma, Tian, Wu, & Ma, 2017; Sasso & Latella, 2018; Zaramela et al, 2019). In contrast, a low‐protein diet was shown to activate immune responses to inhibit the growth of mouse lymphoma, melanoma, and colorectal cancer (Rubio‐Patiño et al, 2018), while the plant‐derived protein (Bonturi et al, 2018; Møller et al, 2019), in particular, the fungal proteins from some mushrooms have been shown to have an effective immunomodulatory effect (Akanbi, Post, & van Putten, 2013; Hassan, Rouf, Tiralongo, May, & Tiralongo, 2015; Hsin et al, 2011), and improvement on gut microbiota (Chen et al, 2017). Dietary fiber can be metabolized by the gut microbiota, and the metabolites can prevent cancer; low fiber intake can cause gut microbiota disorders, leading to many diseases, including colon cancer (Bishehsari et al, 2018).…”