Abstract
Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.
Highlights
Hepatocellular carcinoma (HCC) is the third common lethal human cancer globally, with higher incidence and mortality rates in men than women
A similar effect was observed for the other autophagic proteins, including autophagic regulators may proteins (Atg) 67, p62, and Beclin-1, which substantiates that the derivative might have a better autophagy regulatory activity than curcumin and could contribute to better activity against the HCC cells
The present review focuses on HCC, the third deadly cancer with a poor prognosis due to inefficiency in the treatment
Summary
Hepatocellular carcinoma (HCC) is the third common lethal human cancer globally, with higher incidence and mortality rates in men than women. Polyphenolic compounds show a wide range of biological functions, including antioxidant, antiallergic, anti-inflammatory, antimutagenic, anticarcinogenic, and antiproliferative effects [17,18,19,20] They exhibit co-chemotherapeutic effects by various mechanisms, such as cell cycle alteration, antiproliferation, apoptosis, autophagy, and modulation of various cell signaling pathways [21]. Quercetin induces widespread autophagy in colon epithelial cancer cells, leading to cell cycle arrest and initiation of apoptosis [31] Polyphenols execute their anti-HCC effects through autophagy by interfering with canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) pathways as well as various other signaling, including epidermal growth factor receptor (EGFR)/tyrosine-protein kinase Met (c-Met) signaling pathway, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-related pathway, Janus kinase/signal transducer and activator of transcription pathway, heat shock protein-related pathway, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinases (JNK) pathway, phosphoinositide-3-kinase (PI3K)-phosphatase and tensin homolog-serine/threonine-protein kinase (PTEN)-mammalian target of rapamycin (mTOR), and transforming growth factor-β (TGF-β) pathway.
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