Skip to main content
Log in

The potential protective and therapeutic effects of cannabidiol oil on experimental Leukemia induced by DMBA in male rats

  • Research
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Background

7,12-Dimethylbenzanthracene (DMBA) is a member of the polycyclic aromatic hydrocarbon family. It is a member of the polycyclic aromatic hydrocarbon family. It is a mutagenic, carcinogenic, and immunosuppressor agent. Cannabidiol (CBD) is a phytocannabinoid. It has anticonvulsant, anti-inflammatory, anti-anxiety, antioxidant, and anti-cancer properties. The purpose of this study was to investigate the possible protective and therapeutic benefits of CBD oil in DMBA-induced leukemia in rats.

Method

Experimental animals were divided into six groups of five rats each. Group 1 (normal control) included healthy rats. Group 2 included normal rats that received olive oil. Group 3 included normal rats that received CBD. Group 4 included the DMBA-induced leukemic group. Group 5 (prophylactic group) included rats that received CBD as a prophylaxis before IV injection with DMBA. Group 6 (treated group) included DMBA-induced leukemic rats that received CBD as treatment. Liver functions (total, direct and indirect bilirubin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), albumin, globulin, and albumin globulin ratio) were measured. Superoxide dismutase (SOD) and catalase (CAT) were also measured. Total RNA extraction followed by-real time qRT-PCR gene expression of LC3-II, Beclin, mTOR, and P62 was performed. Histopathological examination of liver and spleen tissues was performed.

Results

Administration of CBD in groups 5 and 6 resulted in a significant improvement of the levels of liver functions compared to the leukemic untreated rats. Also, the levels of catalase and SOD significantly increased after treatment with CBD compared to the leukemic group. After treatment with CBD in groups 5 and 6, there were downregulations in the expression of all studied genes compared to leukemic untreated rats. Treatment with CBD was more statistically effective than prophylactic use.

Conclusion

Administration of CBD resulted in a significant improvement in the biochemical, antioxidant status, morphological, and molecular measures in DMBA-induced leukemia in adult male rats. The therapeutic use was more effective than the prophylactic one.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Available upon a reasonable request.

Abbreviations

DMBA:

7,12-Dimethylbenzanthracene

CBD:

Cannabidiol

LDH:

Lactate dehydrogenase

RBCs:

Red blood cells

Hb:

Hemoglobin

WBCs:

White blood cells count

RDLC:

Relative differential leukocytes count

ADLC:

Absolute differential leukocytes count

ALP:

Alkaline phosphatase

ALT:

Alanine transaminase

AST:

Aspartate aminotransferase

AML:

Acute myeloid leukemia

CML:

Chronic myeloid leukemia

ALL:

Acute lymphoblastic leukemia

CLL:

Chronic lymphocytic leukemia

References

  • Al-Asady AM, Ghaleb IK, Alnasrawi AMAJ, ALhamed TA (2020) Influence of carcinogenic substance (7, 12 dimethylbenz [A] anthracene (DMBA)) on tissue, hematology character and enzyme activity in rat. Indian J Forensic Med Toxicol 14(1):1255–1259. https://doi.org/10.37506/v14/i1/2020/ijfmt/193082

    Article  CAS  Google Scholar 

  • Alexander PS, Michelle M, Brett N, Shaun DR, Eileen AM (2011) Understanding the villain: DMBA-induced preantral ovotoxicity involves selective follicular destruction and primordial follicle activation through PI3K/Akt and mTOR signa. Toxicol Sci 123(2):563–575. https://doi.org/10.1093/toxsci/kfr195

    Article  CAS  Google Scholar 

  • Aliyu A, Shaari M, Mustapha N et al (2019) Some chemical carcinogens for leukaemia induction and their animal models. Ann Res Rev Biol 33(1):1–7. https://doi.org/10.9734/arrb/2019/v33i130108

    Article  CAS  Google Scholar 

  • Arber DA, Orazi A, Hasserjian R et al (2016) The revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405

    Article  CAS  PubMed  Google Scholar 

  • Arora R, Bhushan S, Kumar R, Mannan R, Kaur P, Singh AP, Singh B, Vig AP, Sharma D, Arora S (2014) Hepatic dysfunction induced by 7, 12-dimethylbenz(α)anthracene and its obviation with erucin using enzymatic and histological changes as indicators. PLoS One 9(11):e112614

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Atalay S, Jarocka-Karpowicz I, Skrzydlewska E (2020) Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants 9:21–41

    Article  CAS  Google Scholar 

  • Bancroft JD, Gamble M (2008) Theory and practice of histological technique, 4th edition. Churchil Livingston, New York, London, San Francisco, Tokyo

  • Belson M, Kingsley B, Holmes A (2007) Risk factors for acute leukemia in children: a review. Environ Health Perspect 115(1):138–145

    Article  CAS  PubMed  Google Scholar 

  • Brunetti P, Lo Faro AF, Pirani F et al (2020) Pharmacology and legal status of cannabidiol. Ann Ist Super Sanita 56(3):285–291. https://doi.org/10.4415/ANN_20_03_06

    Article  CAS  PubMed  Google Scholar 

  • Dariš B, Tancer Verboten M, Knez Ž, Ferk P (2019) Cannabinoids in cancer treatment: therapeutic potential and legislation. Bosn J Basic Med Sci 19(1):14–23. https://doi.org/10.17305/bjbms.2018.3532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis AS, Viera AJ, Mead MD (2014) Leukemia: an overview for primary care. Am Fam Physician 89(9):731–738

    PubMed  Google Scholar 

  • Dimitrova-Shumkovska J, Veenman L, Ristoski T, Leschiner S, Gavish M (2010) Decreases in binding capacity of the mitochondrial 18 kda translocator protein accompany oxidative stress and pathological signs in rat liver after DMBA exposure. Toxicol 38(6):957–968. https://doi.org/10.1177/0192623310379137

    Article  CAS  Google Scholar 

  • Fan L, Yin S, Zhang E, Hu H (2018) Role of p62 in the regulation of cell death induction. Apoptosis. 23(3–4):187–193. https://doi.org/10.1007/s10495-018-1445-z

    Article  CAS  PubMed  Google Scholar 

  • Feldman BF, Zinkl JG, Jain NC (2000) Schalm's veterinary hematology, 5th edition. Lippincott Williams and Wilkins A Wolters Company Philadelphia, Baltimore, New York, London, pp: 1219-1224

  • Fu Z, Zhao PY, Yang XP et al (2023) Cannabidiol regulates apoptosis and autophagy in inflammation and cancer: A review. Front Pharmacol 14:1094020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J (2007) Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res 1134:162–170

    Article  PubMed  Google Scholar 

  • Hernández-Tiedra S, Fabriàs G, Dávila D, Salanueva ÍJ, Casas J, Montes LR, Antón Z, García-Taboada E, Salazar-Roa M, Lorente M et al (2016) Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12:2213–2229

    Article  PubMed  PubMed Central  Google Scholar 

  • Hinz B, Ramer R (2022) Cannabinoids as anticancer drugs: current status of preclinical research. Brit J Cancer 127:1–13. https://doi.org/10.1038/s41416-022-01727-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huggins CB, Sugiyama T (1966) Induction of leukemia in rat by pulse doses of 7,12-dimethylbenz(a)anthracene. Proc Natl Acad Sci U S A 55(1):74–81. https://doi.org/10.1073/pnas.55.1.74

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Hussein NAEM, El-Toukhy MAEF, Kazem AH, Ali MES, Ahmad MAER, Ghazy HMR, El-Din AMG (2014) Protective and therapeutic effects of cannabis plant extract on liver cancer induced by dimethylnitrosamine in mice. Alex J Med 50(3):241–251

    Google Scholar 

  • Jeong S, Yun HK, Jeong YA et al (2019) Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells. Cancer Lett 447:12–23

    Article  CAS  PubMed  Google Scholar 

  • Juknat A, Pietr M, Kozela E et al (2012) Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and D9-tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol. 165:2512–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kabeel MM, Ghoneim AM, Mansy SE (2018) Anti-leukemic activity of a four-plantmixture in a leukemic rat model. J Basic Appl Zool 79:7. https://doi.org/10.1186/s41936-018-0019-5

    Article  Google Scholar 

  • Kalenderoglou N, Macpherson T, Wright KL (2017) Cannabidiol reduces leukemic cell size—but is it important? Front Pharmacol 8:144

    Article  PubMed  PubMed Central  Google Scholar 

  • Lagunas-Rangel FA, Chavez-Valencia V (2017) FLT3–ITD and its current role in acute myeloid leukaemia. Med Oncol 34(6):114. https://doi.org/10.1007/s12032-017-0970-x

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  • Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D (2006) The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 63:2057–2066

    Article  CAS  PubMed  Google Scholar 

  • McAllister SD, Soroceanu L, Desprez P-Y (2015) The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol 10:255–267

    Article  PubMed  PubMed Central  Google Scholar 

  • McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M (2006) Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70:897–908

    Article  CAS  PubMed  Google Scholar 

  • Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 42:11S-19S

    Article  CAS  PubMed  Google Scholar 

  • Mlost J, Bryk M, Starowicz K (2020) Cannabidiol for pain treatment: focus on pharmacology and mechanism of action. Int J Mol Sci 21:8870. https://doi.org/10.3390/ijms21228870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore CF, Weerts EM (2022) Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations. Psychopharmacology (Berl) 239(5):1397–1408

    Article  CAS  PubMed  Google Scholar 

  • Moreno E, Cavic M, Krivokuca A, Casadó V, Canela E (2019) The endocannabinoid system as a target in cancer diseases: are we there yet? Front Pharmacol 10:339. https://doi.org/10.3389/fphar.2019.00339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muqbil I, Banu N (2006) Enhancement of pro-oxidant effect of 7,12-dimethylbenz (a) anthracene (DMBA) in rats by pre-exposure to restraint stress. Cancer Lett 240(2):213–220. https://doi.org/10.1016/j.canlet.2005.09.008

    Article  CAS  PubMed  Google Scholar 

  • Nahler G (2022) Cannabidiol and other phytocannabinoids as cancer therapeutics. Pharmaceut Med 36(2):99–129

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olivas-Aguirre M, Torres-Lopez L, Valle-Reyes JS, Hernandez-Cruz A, Pottosin I, Dobrovinskaya O (2019) Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia. Cell Death Dis 10:779

    Article  PubMed  PubMed Central  Google Scholar 

  • Paliwal R, Sharma V, Pracheta, Sharma S, Yadav S, Sharma SH (2011) Antinephrotoxic effect of administration of MoringaOleifera Lam in amelioration of DMBA induced renal carcinogenesis in Swiss Albino mice. Biol Med 3:27–35

    Google Scholar 

  • Quentmeier H, Eberth S, Romani J et al (2011) BCR-ABL1-independent PI3 kinase activation causing imatinib-resistance. J Hematol Oncol 4:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajesh M, Mukhopadhyay P, Bátkai S et al (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol 56:2115–2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salazar M, Carracedo A, Salanueva ÍJ, Hernández-Tiedra S, Lorente M et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Investig 119(5):1359–1372. https://doi.org/10.1172/jci37948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salcin H, Goker Bagca B, Alcitepe I et al (2022) Investigating the effects of a synthetic cannabinoid on the pathogenesis of leukemia and leukemic stem cells: a new therapeutic approach. Cannabis Cannabinoid Res. https://doi.org/10.1089/can.2021.0180

  • Scott KA, Dalgleish AG, Liu WM (2017) Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration. Int J Oncol 51:369–377

    Article  CAS  PubMed  Google Scholar 

  • Selamoglu Z (2018) 7, 12-Dimethylbenz[a]anthracene toxicity and cancer. SF Oncol Can Res J 2:2

    Google Scholar 

  • Seltzer ES, Watters AK, MacKenzie D et al (2020) Cannabidiol (CBD) as a promising anti-cancer drug. Cancers (Basel) 12(11):3203

    Article  CAS  PubMed  Google Scholar 

  • Simmerman E, Qin X, Yu JC, Baban B (2019) Cannabinoids as a potential new and novel treatment for melanoma: a pilot study in a murine model. J Surg Res 235:210–215

    Article  CAS  PubMed  Google Scholar 

  • Śledziński P, Zeyland J, Słomski R, Nowak A (2018) The current state and future perspectives of cannabinoids in cancer biology. Cancer Med 7(3):765–775

    Article  PubMed  PubMed Central  Google Scholar 

  • Soroceanu L, Murase R, Limbad C et al (2013) Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res 73(5):1559–1569

    Article  CAS  PubMed  Google Scholar 

  • Soto-Mercado V, Mendivil-Perez M, Jimenez-Del-Rio M, Fox JE, Velez-Pardo C (2020) Cannabinoid CP55940 selectively induces apoptosis in Jurkat cells and in ex vivo T-cell acute lymphoblastic leukemia through H (2)O(2) signaling mechanism. Leuk Res 95:106389

    Article  CAS  PubMed  Google Scholar 

  • Sun S, Hu F, Wu J, Zhang S (2017) Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons. Redox Biol 11:577–585

    Article  CAS  PubMed  Google Scholar 

  • Tebbi CK (2021) Etiology of Acute Leukemia: A Review. 13(9): 2256. https://doi.org/10.3390/cancers13092256

  • Thakkar K, Ruan CH, Ruan KH (2021) Recent advances of cannabidiol studies in medicinal chemistry, pharmacology and therapeutics. Future Med Chem 13(22):1935–1937. https://doi.org/10.4155/fmc-2021-0125

    Article  CAS  PubMed  Google Scholar 

  • Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G, Díaz-Laviada I (2011) Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18:1099–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Velasco G, Sánchez C, Guzmán M (2016) Anticancer mechanisms of cannabinoids. Curr Oncol 23:23–32

    Article  Google Scholar 

  • Wang Y, Mukhopadhyay P, Cao Z et al (2017) Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury. Sci Rep 7:1–1

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

N.A.S., S.I. E. D. and  S.H. wrote the main manuscript text. T.K., R.S., and S.M.A. prepared figures. All authors reviewed the manuscript. The authors declare that all data  were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Samia Hussein.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the Institutional Animal Care and Use Committee (ZU-IACUC/1/F/193/2023)

Consent for publication

Not applicable

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soliman, N.A., El Dahmy, S.I., Khamis, T. et al. The potential protective and therapeutic effects of cannabidiol oil on experimental Leukemia induced by DMBA in male rats. Naunyn-Schmiedeberg's Arch Pharmacol 397, 2389–2400 (2024). https://doi.org/10.1007/s00210-023-02737-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-023-02737-6

Keywords

Navigation