Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway

Abstract

Osteosarcoma becomes the second leading cause of cancer death in the younger population. Current outcomes of chemotherapy on osteosarcoma were unsatisfactory to date, demanding development of effective therapies. Tea is a commonly used beverage beneficial to human health. As a major component of tea, theabrownin has been reported to possess anti‐cancer activity. To evaluate its anti‐osteosarcoma effect, we established a xenograft model of zebrafish and employed U2OS cells for in vivo and in vitro assays. The animal data showed that TB significantly inhibited the tumour growth with stronger effect than that of chemotherapy. The cellular data confirmed that TB‐triggered DNA damage and induced apoptosis of U2OS cells by regulation of Mki67, PARP, caspase 3 and H2AX, and Western blot assay showed an activation of p53 signalling pathway. When P53 was knocked down by siRNA, the subsequent downstream signalling was blocked, indicating a p53‐dependent mechanism of TB on U2OS cells (p53 wt). Using osteosarcoma cell lines with p53 mutations (HOS, SAOS‐2 and MG63), we found that TB exerted stronger inhibitory effect on U2OS cells than that on p53‐mut cell lines, but it also exerted obvious effect on SAOS‐2 cells (p53 null), suggesting an activation of p53‐independent pathway in the p53‐null cells. Interestingly, theabrownin was found to have no toxicity on normal tissue in vivo and could even increase the viability of p53‐wt normal cells. In sum, theabrownin could trigger DNA damage and induce apoptosis on U2OS cells via a p53‐dependent mechanism, being a promising candidate for osteosarcoma therapy.

<p>Water Extract of Sporoderm-Broken Spores of <em>Ganoderma lucidum</em> Induces Osteosarcoma Apoptosis and Restricts Autophagic Flux</p>

“…HOS, SAOS-2, and MG63 are osteosarcoma cell lines with p53 mutations, while U2-OS is a p53wt cell line. 37,38 Due to the limitations of time and budget, we selected two representative cells (HOS and U2-OS) for subsequent experiments. Ganoderma lucidum, containing a variety of active ingredients, has different targets, which leads to the activation or inhibition of various signaling pathways in cells, thus increasing the difficulty of signaling pathway exploration.…”

Theaflavin Induces Apoptosis of A375 Human Melanoma Cells and Inhibits Tumor Growth in Xenograft Zebrafishes Through P53- and JNK-Related Mechanism

“…The inhibitory rate was higher than that of cisplatin, indicating that TF was more effective than cisplatin within their respective safe dose range. Moreover, the inhibitory rate was higher than that of another tea pigment (theabrownin) ( Jin et al, 2018 ), suggesting TF as the most effective component of tea. However, the effective in vivo dose range (1.3 to 3.9 μM) of TF is much lower than its effective in vitro dose range (96.8 to 774.4 μM).…”

“…TF were dissolved into each well at 0, 3.47, 10.4, 31.25, 62.5, 125, 250, 500, 1,000, and 2,000 μg/ml, respectively, for 24 h. Afterwards, fishes in each group were observed under a stereoscopic microscope to record mortality and adverse events. As described by our previous study, no observed adverse effect level (NOAEL) of TF was estimated, and 1/9 NOAEL, 1/3 NOAEL and NOAEL were applied as the low, middle, and high doses for the following experiment ( Jin et al, 2018 ).…”

“…Tea leaves have been characterized as a TCM herb with anti-phlegm and anti-toxic properties, indicating its anti-cancer potential. Modern studies have reported that tea drink is effective in preventing and treating cancers ( Jin et al, 2018 ). Recently, tea polyphenols have been found to possess anti-cancer activity, which have superior effect to tea drink ( Mao et al, 2019 ).…”

Structural Characteristics and Hypolipidemic Activity of Theabrownins from Dark Tea Fermented by Single Species Eurotium cristatum PW-1

“…In the past few years, studies have provided important information on the functions and bioactivities of theabrownins, demonstrating that they can inhibit the activity of α-glucosidase in vitro, decrease blood glucose levels and increase glucose tolerance in mice under hyperglycemic stress [7]. Additionally, they exhibit anti-osteoporotic [8], anti-tumor [9][10][11], and hypolipidemic effects in vitro and in vivo [12][13][14][15]. Nonetheless, because of its complexity, the physicochemical properties of theabrownins are rarely studied.…”