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Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy

Cancer and Metastasis Reviews (2023)Cite this article

Abstract

Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects. Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality. Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis. However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC. This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime.

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Fig. 1

Abbreviations

Ag2:

Angiopoietin-2

AKT:

Protein kinase B

ATF-4:

Activating transcription factor 4

BAD:

Bcl2-associated agonist of cell death protein

BAX:

Bcl2-associated X protein

CACS:

Cancer anorexia-cachexia syndrome

CB1:

Cannabinoid receptor type1

CB2:

Cannabinoid receptor type2

CBC:

Cannabichromene

CBD:

Cannabidiol

CBN:

Cannabinol

CBDA:

Cannabidiolic acid

CBG:

Cannabigerol

CD147:

Cluster of differentiation 147

CD31:

Cluster of differentiation 31

CD45:

Cluster of differentiation 45

Cdc2:

Cell division cycle protein 2

CDH1:

Gene encoded E-cadherin

CDH2:

Gene encoded N-cadherin

Cdk4/2:

Cyclin-dependent kinase 4/2

CHOP:

C/EBP homologous protein

COX2:

Cyclooxygenase 2

CP55940:

Synthetic cannabinoid

CRC:

Colorectal cancer

CXCR4:

C-X-C chemokine receptor type 4

DRAM:

DNA damage-regulated autophagy modulator

ECS:

Endocannabinoid systems

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

GBM:

Glioblastoma multiforme

GPCR:

G protein-coupled receptor

GRP78:

Glucose-regulated protein

GSH:

Glutathione

H2AX:

H2A histone family member X

HER2:

Human epidermal growth factor receptor 2

5-HT3:

5-hydroxytryptamine 3

ICAM-1:

Intercellular adhesion molecule 1

IL-10:

Interleukin 10

IL-4:

Interleukin 4

JNK:

c-Jun N-terminal kinase

JunD:

AP-1 transcription factor

LAK-1:

Lymphokine-activated killer-1

MAPK:

Mitogen-activated protein kinases

MM:

Multiple myeloma

MMP2:

Matrix metalloproteinase-2

MMP2/9:

Matrix metalloproteinase-2/9

MMP9:

Matrix metalloproteinase-9

mTOR:

Mammalian target of rapamycin

NOXA:

A proapoptotic member of BH3-only Bcl-2 family proteins

NSCLC:

Non-small-cell lung cancer

p21:

Cyclin-dependent kinase inhibitor 1

p27:

Cyclin-dependent kinase inhibitor 1B

p38-MAPK:

p38 mitogen-activated protein kinase

p42/44:

Mitogen-activated protein kinase;

PAK1:

p-21 activated kinase 1

Parkin:

Cytosolic E3 ubiquitin ligase

PC:

Pancreatic cancer

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed cell death ligand-1

PI3K:

Phosphatidylinositol-3 kinase

PINK1:

PTEN-induced putative kinase 1

PPARγ:

Peroxisome proliferator-activated receptor γ

pRb:

Phosphoretinoblastoma protein

PSC:

Pancreatic stellate cells

PUMA:

p53 upregulated modulator of apoptosis

QOL:

Quality of life

RAD51:

Gene encode a DNA repair protein

RAS:

Rat sarcoma virus

TGF-β:

Transforming growth factor

THC:

Tetrahydrocannabinol

TIMP1:

Tissue inhibitors of metalloproteinases1

Tes:

Testin

TME:

Tumor microenvironment

TMZ:

Temozolomide

TRB3:

Tribbles-like protein 3

TRPV1:

Transient receptor potential vanilloid-1

VEGF:

Vascular endothelial growth factors

VEGFR:

Vascular endothelial growth factor receptor

VIM:

Vimentin

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Acknowledgements

The authors would like to acknowledge the Council of Scientific and Industrial Research, India (OLP-0106). The institutional manuscript number is CSIR-NBRI_MS/2022/09/02.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79410, USA

    Prateeksha Prateeksha

  2. Herbal Nanobiotechnology Lab, Pharmacology Division, CSIR-National Botanical Research Institute, Lucknow, 226001, India

    Vivek K. Sharma & Brahma N. Singh

  3. Department of Botany, Faculty of Science, Banaras Hindu University, Varanasi, 221005, India

    Shiv M. Singh

  4. Haute Ecole Provinciale de Hainaut-Condorcet, Rue de la Sucrerie, 7800, Mons, ATH, Belgium

    Minaxi Sharma

  5. Washington University, School of Medicine, Saint Louis, MO 63108, USA

    Deepti Diwan

  6. Genetics Department, Faculty of Agriculture, Beni-Suef University, Beni-Suef, 62521, Egypt

    Abd El-Latif Hesham

  7. Natural Product-cum-Nano Lab, Division of Biochemistry, Faculty of Basic Sciences, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, Main Campus Chatha, Jammu and Kashmir, 180009, India

    Sanjay Guleria

  8. Department of Bioengineering and Alcoholic Drink Technology, Institute of Food Science and Technology, Hungarian University of Agriculture and Life Sciences, Ménesi út 45, Budapest, H-1118, Hungary

    Quang D. Nguyen

  9. Biorefining and Advanced Materials Research Center, SRUC, Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK

    Vijai K. Gupta

  10. Center for Safe and Improved Food, SRUC, Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK

    Vijai K. Gupta

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  1. Prateeksha Prateeksha
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Prateeksha, P., Sharma, V.K., Singh, S.M. et al. Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy. Cancer Metastasis Rev (2023). https://doi.org/10.1007/s10555-023-10078-2

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Keywords

  • Tetrahydrocannabinols
  • Cannabis
  • Cannabinoid receptors
  • Cannabimimetic properties
  • Metastasis
  • Angiogenesis
  • Antitumor