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Ginsenoside Rg5 as an anticancer drug: a comprehensive review on mechanisms, structure–activity relationship, and prospects for clinical advancement

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Abstract

Cancer remains one of the leading causes of death in the world. Despite the considerable success of conventional treatment strategies, the incidence and mortality rates are still high, making developing new effective anticancer therapies an urgent priority. Ginsenoside Rg5 (Rg5) is a minor ginsenoside constituent obtained exclusively from ginseng species and is known for its broad spectrum of pharmacological activities. This article aimed to comprehensively review the anticancer properties of Rg5, focusing on action mechanisms, structure–activity relationship (SAR), and pharmacokinetics attributes. The in vitro and in vivo activities of Rg5 have been proven against several cancer types, such as breast, liver, lung, bone, and gastrointestinal (GI) cancers. The modulation of multiple signaling pathways critical for cancer growth and survival mediates these activities. Nevertheless, human clinical studies of Rg5 have not been addressed before, and there is still considerable ambiguity regarding its pharmacokinetics properties. In addition, a significant shortage in the structure–activity relationship (SAR) of Rg5 has been identified. Therefore, future efforts should focus on further optimization by performing extensive SAR studies to uncover the structural features essential for the potent anticancer activity of Rg5. Thus, this review highlights the value of Rg5 as a potential anticancer drug candidate and identifies the research areas requiring more investigation.

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Abbreviations

Akt:

Group of serine-threonine enzyme

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

AMPK:

AMP-activated protein kinase

AMP:

Adenosine monophosphate

ATM:

Ataxia telangiectasia mutation

Bad:

Proapoptotic BH3-only protein

Bak:

Bcl-2 homologous antagonist/killer

Bax:

Bcl-2 associated X-protein

Bcl-2:

B-cell lymphoma-2

Bcl-xL:

B-cell lymphoma extra large

BUN:

Blood urea nitrogen

Ca2+ :

Calcium cation

Cdc:

Cell division cycle

CDK 4:

Cyclin-dependent kinase-4

Cyclin B1:

Regulatory protein in mitosis of the cell cycle from G2 to M phase

Cyclin D1:

A regulator of cell cycle progression, oncogenic driver

Cyclin E2:

Regulatory protein in mitosis of the cell cycle, i.e. S-phase

Cyp450:

Cytochrome P450

Cyt C:

Cytochrome C

EphA2:

Erythropoietin-producing hepatocellular receptor A2

Erk:

Extracellular signal-regulated kinase

ESR2:

Estrogen receptor 2

GABA:

Gamma-aminobutyric acid

Ginsenoside Rg5:

Rg5

GIT:

Gastrointestinal tract

HSP:

Heat shock protein

IAPs:

Inhibitors of apoptosis proteins

IR:

Infrared

MDM2:

Mouse double minute 2

MS:

Mass spectrometry

mTOR:

Mammalian target of rapamycin

NAPQI:

N-acetyl-p-benzoquinone imine

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NIDDM:

Non-insulin-dependent diabetes mellitus

NLRP3:

NOD-like receptor family pyrin domain-containing 3

NMR:

Nuclear magnetic resonance

PARP:

Poly-adenosine diphosphate-ribose polymerase

p21:

Polyclonal-21 antibody

p15:

Polyclonal-15 antibody

p26:

Polyclonal-26 antibody

p70S6k:

P70 ribosomal s6 kinase

p53:

Polyclonal-53 antibody

PI3K:

Phosphatidyl inositol-3-kinase

PARP:

Poly-adenosine diphosphate-ribose polymerase

PPD:

Protopanaxadiol

PPT:

Protopanaxatriol

Ras:

Ras oncogenes

ROS:

Reactive oxygen species

SAR:

Structure–activity relationship

S6:

Serine-threonine protein-6

Smad 2/3:

Suppressor of mothers against decapentaplegic 2/3

TGF-β:

Transforming growth factor-beta:

T max :

Peak time

V d :

Volume of distribution

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf, Saudi Arabia

    Tilal Elsaman & Magdi Awadalla Mohamed

  2. Department of Horticulture, Faculty of Agriculture, University of Khartoum, Shambat, 13314, Khartoum North, Sudan

    Ali Mahmoud Muddathir

  3. Faculty of Pharmacy, University of Science and Technology, Omdurman, Sudan

    Ebtihal A. M. Mohieldin

  4. Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University (Bogor Agricultural University), Bogor, Indonesia

    Irmanida Batubara & Shadila Fira Asoka

  5. Division of Pharmacology, School of Veterinary Medicine and Biomedical Science, IPB University, Jln Agathis Dramaga, Bogor, West Java, 16680, Indonesia

    Min Rahminiwati

  6. Tropical Biopharmaca Research Center, IPB University, Jl. Taman Kencana No. 3, Bogor, West Java, 16128, Indonesia

    Min Rahminiwati

  7. Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan

    Kosei Yamauchi

  8. Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar

    Dietrich Büsselberg

  9. Pharmacognosy Research and Herbal Analysis Services UK, Central Avenue , Chatham, Kent, ME4 4TB, UK

    Solomon Habtemariam

  10. Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador

    Javad Sharifi-Rad

  11. Tropical Biopharmaca Research Center, IPB University (Bogor Agricultural University), Bogor, Indonesia

    Irmanida Batubara & Shadila Fira Asoka

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  1. Tilal Elsaman
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  2. Ali Mahmoud Muddathir
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  3. Ebtihal A. M. Mohieldin
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  7. Magdi Awadalla Mohamed
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  8. Shadila Fira Asoka
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  9. Dietrich Büsselberg
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  11. Javad Sharifi-Rad
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Contributions

Conceptualization and design were performed by J.S.-R.; investigation, data curation, and writing were performed by T.E., A.M.M., E.A. M. M., I.B., M.R., K.Y., M.A.M., S.F.A.; validation, review, and editing were performed by D.B., S.H., J.S.-R. All the authors contributed equally, read, and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Javad Sharifi-Rad.

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Elsaman, T., Muddathir, A.M., Mohieldin, E.A.M. et al. Ginsenoside Rg5 as an anticancer drug: a comprehensive review on mechanisms, structure–activity relationship, and prospects for clinical advancement. Pharmacol. Rep 76, 287–306 (2024). https://doi.org/10.1007/s43440-024-00586-5

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