Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL

Abstract

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The aim of this work was to analyze the improvement of the anticancer effect of rhsTRAIL (recombinant human soluble TRAIL) by nine flavones: 5-Hydroxyflavone, 6-Hydroxyflavone, 7-Hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5-butyryloxyflavone, 6-acetoxyflavone, 6-butyryloxyflavone, 7-acetoxyflavone and 7-butyryloxyflavone. We examined the cytotoxic and apoptotic effects of rhsTRAIL enhanced by novel structurally-related flavones on SW480 and SW620 colon cancer cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, the lactate dehydrogenase assay and annexin V-FITC fluorescence staining. We observed a slight difference in the activities of the flavones that was dependent on their chemical structure. Our study indicates that all nine flavones significantly augment cell death by rhsTRAIL (cytotoxicity range 36.8 ± 1.7%–91.4 ± 1.7%; apoptosis increase of 33.0 ± 0.7%–78.5 ± 0.9%). Our study demonstrates the potential use of tested flavones in TRAIL-based anticancer therapy and prevention.

Chrysin induces autophagy through the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in endometrial cancer

“…However, certain types of cancer, including gliomas, are resistant to TRAIL-induced cell death ( 26 ). Chrysin has been shown to overcome TRAIL resistance in breast, pancreatic, cervical, colon, prostate and bladder cancer, as well as in hepatoma and melanoma cells ( 27 ). Thus, chrysin represents a potential therapeutic target for the development of clinical applications.…”

TRAIL-Sensitizing Effects of Flavonoids in Cancer

“…In addition to apigenin, luteolin, and chrysin, other flavones have been reported to exert TRAIL-sensitizing effects in different types of cancer [54].…”

Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies

“…Their results showed that chrysin, not the 5-FU combination, induces reactive oxygen species (ROS) generation, and consequently, inhibits the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR; Lin et al, 2018). Nine novel structurally related flavones, 5-hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5-butyryloxyflavone, 6-butyryloxyflavone, 6-acetoxyflavone, 7-butyryloxyflavone, and 7-acetoxyflavone significantly augment tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in SW480 and SW620 colon cancer cells (Bronikowska et al, 2017).…”

“…Their results showed that chrysin, not the 5‐FU combination, induces reactive oxygen species (ROS) generation, and consequently, inhibits the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR; Lin et al, ). Nine novel structurally related flavones, 5‐hydroxyflavone, 6‐hydroxyflavone, 7‐hydroxyflavone and their new synthetic derivatives 5‐acetoxyflavone, 5‐butyryloxyflavone, 6‐butyryloxyflavone, 6‐acetoxyflavone, 7‐butyryloxyflavone, and 7‐acetoxyflavone significantly augment tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in SW480 and SW620 colon cancer cells (Bronikowska et al, ). Another flavone baicalein, 5,6,7‐trihydroxyflavone, has been shown to inhibit the ERK signaling pathways, downregulate Ezrin and upregulate P53 pathway‐related proteins, DEPP and Gadd45a to suppress human colorectal cell invasion and proliferation and an induction of a marked apoptotic response (Chai, Xu, & Yan, ; Z. Chen, Hou, Gao, Song, & Feng, ; Su et al, ).…”