The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

Abstract

Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.

Flavonoids as Putative Inducers of the Transcription Factors Nrf2, FoxO, and PPARγ

“…Moreover, it was reported that fisetin stimulated Nrf2 signalling, ERK/MAPK signalling, and kinases involved in cell cycle regulation in vitro [44]. Of interest, flavonoids were shown to influence various cyclin-dependent kinases [45], mitogen-activated protein kinases (MAPK), protein kinase Akt, and FoxO signalling [46] and to counteract inflammation [47-49].…”

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

“…13) Excessive evidence has demonstrated that fisetin could inhibit various chronic inflammation-related conditions, cell proliferation, oxidative stress, and cardiac hypertrophy. [14][15][16][17] Meanwhile, fisetin significantly attenuates the ischemia/reperfusion (I/R)-induced myocardial tissue injury by suppressing mitochondrial oxidative stress, and FISETIN REDUCES ATRIAL FIBRILLATION VULNERABILITY Table I. Information of Primers for RT-PCR…”

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

“…However, poor bioavailability, rapid metabolization due to lipophilic, and highly insoluble nature, being effective in high doses, are among the major problems encountered by using curcumin clinically . Flavonoids are other well‐known and well‐studied natural product modulators that include flavonols, flavones, isoflavones, flavanols, flavanolols, flavanones, and chalcones . In addition to the fact that these compounds are modulators of ABC drug transporters, it is reported that they also alter the overall pharmacokinetics, including drug absorption, penetration, and elimination .…”

“…97 Flavonoids are other well-known and well-studied natural product modulators that include flavonols, flavones, isoflavones, flavanols, flavanolols, flavanones, and chalcones. 98 In addition to the fact that these compounds are modulators of ABC drug transporters, it is reported that they also alter the overall pharmacokinetics, including drug absorption, penetration, and elimination. 99 Therefore, it is not surprising that the result of such interaction is not only the inhibition of transporters; some flavonoids can stimulate (rather than inhibit) ABC transporters, depending on the substrate of interest.…”