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Review
. 2022 Nov 8;23(22):13689.
doi: 10.3390/ijms232213689.

Mechanism of Resveratrol-Induced Programmed Cell Death and New Drug Discovery against Cancer: A Review

Jung Yoon Jang  1 , Eunok Im  1 , Nam Deuk Kim  1
Affiliations
Review

Mechanism of Resveratrol-Induced Programmed Cell Death and New Drug Discovery against Cancer: A Review

Jung Yoon Jang et al. Int J Mol Sci. .

Abstract

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes, red wine, peanuts, and apples, has been reported to exhibit a wide range of biological and pharmacological properties. In addition, resveratrol has been reported to intervene in multiple stages of carcinogenesis. It has also been known to kill several human cancer cells through programmed cell death (PCD) mechanisms such as apoptosis, autophagy, and necroptosis. However, resveratrol has limitations in its use as an anticancer agent because it is susceptible to photoisomerization owing to its unstable double bond, short half-life, and is rapidly metabolized and eliminated. Trans-(E)-resveratrol is nontoxic, and has several biological and pharmacological activities. However, little is known about the pharmacological properties of the photoisomerized cis-(Z)-resveratrol. Therefore, many studies on resveratrol derivatives and analogues that can overcome the shortcomings of resveratrol and increase its anticancer activity are underway. This review comprehensively summarizes the literature related to resveratrol-induced PCD, such as apoptosis, autophagy, necroptosis, and the development status of synthetic resveratrol derivatives and analogues as novel anticancer drugs.

Keywords: apoptosis; autophagy; molecular mechanisms; necroptosis; resveratrol; resveratrol derivatives and analogues.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Resveratrol isomerization.
Figure 2
Figure 2
Physiological functions of resveratrol.
Figure 3
Figure 3
Structures of synthetic resveratrol derivatives. (A) derivative 2. (B) PMS, 2,3′,4,4′,5′-pentamethoxy-trans-stilbene. (C) TMS1, trans-3,5,4′-trimethoxystilbene. (D) Res-006, 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene. (E) PHS, 3,3′,4,5,5′-pentahydroxy-trans-stilbene. (F) 3,3′,4,4𠌩-THS, 3,3′,4,4′-tetrahydroxy-trans-stilbene.
Figure 4
Figure 4
Structures of synthetic resveratrol analogues. (A) TMS2, (Z)-3,4,5,4′-trans-tetramethoxystilbene. (B) SS28, (E)-1,2,3-trimethoxy-5-(4-methylstyryl)benzene. (C) compound 1, (E)-4,4′-(ethene-1,2-diyl)bis(3-methylphenol). (D) TRES, 3,5,4′-tri-O-acetyl-trihydroxystilbene. (E) 3,4,4′-THS, 3,4,4′-trihydroxy-trans-stilbene. (F) DHS, 4,4′-dihydroxy-trans-stilbene. (G) HS-1793, 4-(6-hydroxy-2-naphthyl)-1,3-benzenediol. (H) DIG, 3,5-O-digalloyl-resveratrol. (I) DMU-212, 3,4,4′,5-tetramethoxystilbene. (J) DMU-281, 4-hydroxy-3,4,5-trimetoxystilbene. (K) HPIMBD, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol}. (L) TIMBD, 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}. (M) 3,4,4′-tri-MS, 3,4,4′-trimethoxy-trans-stilbenes. (N) 3,4,2′,4′-tetra-MS, 3,4,2′,4′-tetramethoxy-trans- stilbenes.
Figure 4
Figure 4
Structures of synthetic resveratrol analogues. (A) TMS2, (Z)-3,4,5,4′-trans-tetramethoxystilbene. (B) SS28, (E)-1,2,3-trimethoxy-5-(4-methylstyryl)benzene. (C) compound 1, (E)-4,4′-(ethene-1,2-diyl)bis(3-methylphenol). (D) TRES, 3,5,4′-tri-O-acetyl-trihydroxystilbene. (E) 3,4,4′-THS, 3,4,4′-trihydroxy-trans-stilbene. (F) DHS, 4,4′-dihydroxy-trans-stilbene. (G) HS-1793, 4-(6-hydroxy-2-naphthyl)-1,3-benzenediol. (H) DIG, 3,5-O-digalloyl-resveratrol. (I) DMU-212, 3,4,4′,5-tetramethoxystilbene. (J) DMU-281, 4-hydroxy-3,4,5-trimetoxystilbene. (K) HPIMBD, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol}. (L) TIMBD, 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}. (M) 3,4,4′-tri-MS, 3,4,4′-trimethoxy-trans-stilbenes. (N) 3,4,2′,4′-tetra-MS, 3,4,2′,4′-tetramethoxy-trans- stilbenes.
Figure 5
Figure 5
Mechanisms of PCD induction by resveratrol in cancer cells. AIF, apoptosis-inducing factor; AKT, protein kinase B; AMPK, 5′ adenosine monophosphate-activated protein kinase; Apaf-1, apoptotic protease activating factor-1; Atg, autophagy related; Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2-associated X protein; Bcl-xL, B-cell lymphoma extra-large; Bcl-2, B-cell lymphoma-2; Bid, BH3-interacting-domain death agonist; COX-2, cyclooxygenase-2; Cyt c, cytochrome c; DIRAS3, GTP-binding protein Di-Ras3; Endo G, endonuclease G; ERK, extracellular signal-regulated protein kinases; ER stress, endoplasmic reticulum stress; FADD, FAS-associated death domain protein; FasL, apoptosis-stimulating fragment (Fas) ligand; FOXO3, forkhead box O3; GSK3β, glycogen synthase kinase 3 beta; JAK, Janus kinase; JNK, c-Jun N-terminal kinases; LC3, microtubule-associated proteins 1A/1B light chain 3; Mcl-1, myeloid cell leukemia-1; MEK, mitogen-activated protein kinase; MLKL, mixed lineage kinase domain-like protein; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; p70S6K, ribosomal protein S6 kinase; RIPK, receptor-interacting serine/threonine protein kinase; RTK, receptor tyrosine kinase; SIRT, sirtuin; STAT3, signal transducer and activator of transcription 3; TNFR, tumor necrosis factor receptor; TNF-α, tumor necrosis factor-α; TRAIL, TNF-related apoptosis-inducing ligand; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1.
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