The potential protective and therapeutic effects of cannabidiol oil on experimental Leukemia induced by DMBA in male rats.
Anti-oxidant
Cannabidiol
DMBA
Gene expression
Leukemia
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
04 2024
04 2024
Historique:
received:
29
07
2023
accepted:
20
09
2023
medline:
14
3
2024
pubmed:
15
10
2023
entrez:
14
10
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37837474
doi: 10.1007/s00210-023-02737-6
pii: 10.1007/s00210-023-02737-6
doi:
Substances chimiques
Antioxidants
0
Catalase
EC 1.11.1.6
9,10-Dimethyl-1,2-benzanthracene
57-97-6
Cannabidiol
19GBJ60SN5
Globulins
0
Superoxide Dismutase
EC 1.15.1.1
Albumins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2389-2400Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
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
doi: 10.37506/v14/i1/2020/ijfmt/193082
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
doi: 10.1093/toxsci/kfr195
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
doi: 10.9734/arrb/2019/v33i130108
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
doi: 10.1182/blood-2016-03-643544
pubmed: 27069254
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
doi: 10.1371/journal.pone.0112614
pubmed: 25390337
pmcid: 4229223
Atalay S, Jarocka-Karpowicz I, Skrzydlewska E (2020) Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants 9:21–41
doi: 10.3390/antiox9010021
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
doi: 10.1289/ehp.9023
pubmed: 17366834
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
doi: 10.4415/ANN_20_03_06
pubmed: 32959794
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
doi: 10.17305/bjbms.2018.3532
pubmed: 30172249
pmcid: 6387667
Davis AS, Viera AJ, Mead MD (2014) Leukemia: an overview for primary care. Am Fam Physician 89(9):731–738
pubmed: 24784336
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
doi: 10.1177/0192623310379137
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
doi: 10.1007/s10495-018-1445-z
pubmed: 29480462
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
doi: 10.3389/fphar.2023.1094020
pubmed: 36755953
pmcid: 9899821
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
doi: 10.1016/j.brainres.2006.11.063
pubmed: 17196181
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
doi: 10.1080/15548627.2016.1213927
pubmed: 27635674
pmcid: 5103338
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
doi: 10.1038/s41416-022-01727-4
pubmed: 35277658
pmcid: 9276677
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
doi: 10.1073/pnas.55.1.74
pubmed: 5220873
pmcid: 285757
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
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
doi: 10.1016/j.canlet.2019.01.011
pubmed: 30660647
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
doi: 10.1111/j.1476-5381.2011.01461.x
pubmed: 21542829
pmcid: 3423229
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
doi: 10.1186/s41936-018-0019-5
Kalenderoglou N, Macpherson T, Wright KL (2017) Cannabidiol reduces leukemic cell size—but is it important? Front Pharmacol 8:144
doi: 10.3389/fphar.2017.00144
pubmed: 28392768
pmcid: 5364234
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
doi: 10.1007/s12032-017-0970-x
pubmed: 28470536
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
doi: 10.1006/meth.2001.1262
pubmed: 11846609
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
doi: 10.1007/s00018-006-6156-x
pubmed: 16909207
McAllister SD, Soroceanu L, Desprez P-Y (2015) The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol 10:255–267
doi: 10.1007/s11481-015-9608-y
pubmed: 25916739
pmcid: 4470774
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
doi: 10.1124/mol.106.023937
pubmed: 16754784
Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 42:11S-19S
doi: 10.1002/j.1552-4604.2002.tb05998.x
pubmed: 12412831
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
doi: 10.3390/ijms21228870
pubmed: 33238607
pmcid: 7700528
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
doi: 10.1007/s00213-021-05995-5
pubmed: 34652500
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
doi: 10.3389/fphar.2019.00339
pubmed: 31024307
pmcid: 6459931
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
doi: 10.1016/j.canlet.2005.09.008
pubmed: 16271282
Nahler G (2022) Cannabidiol and other phytocannabinoids as cancer therapeutics. Pharmaceut Med 36(2):99–129
pubmed: 35244889
pmcid: 9021107
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
doi: 10.1038/s41419-019-2024-0
pubmed: 31611561
pmcid: 6791884
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
Quentmeier H, Eberth S, Romani J et al (2011) BCR-ABL1-independent PI3 kinase activation causing imatinib-resistance. J Hematol Oncol 4:6
doi: 10.1186/1756-8722-4-6
pubmed: 21299849
pmcid: 3041785
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
doi: 10.1016/j.jacc.2010.07.033
pubmed: 21144973
pmcid: 3026637
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
doi: 10.1172/jci37948
pubmed: 19425170
pmcid: 2673842
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
doi: 10.3892/ijo.2017.4022
pubmed: 28560402
Selamoglu Z (2018) 7, 12-Dimethylbenz[a]anthracene toxicity and cancer. SF Oncol Can Res J 2:2
Seltzer ES, Watters AK, MacKenzie D et al (2020) Cannabidiol (CBD) as a promising anti-cancer drug. Cancers (Basel) 12(11):3203
doi: 10.3390/cancers12113203
pubmed: 33143283
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
doi: 10.1016/j.jss.2018.08.055
pubmed: 30691796
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
doi: 10.1002/cam4.1312
pubmed: 29473338
pmcid: 5852356
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
doi: 10.1158/0008-5472.CAN-12-1943
pubmed: 23243024
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
doi: 10.1016/j.leukres.2020.106389
pubmed: 32540572
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
doi: 10.1016/j.redox.2016.12.029
pubmed: 28110213
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
doi: 10.4155/fmc-2021-0125
pubmed: 34583522
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
doi: 10.1038/cdd.2011.32
pubmed: 21475304
pmcid: 3131949
Velasco G, Sánchez C, Guzmán M (2016) Anticancer mechanisms of cannabinoids. Curr Oncol 23:23–32
doi: 10.3747/co.23.3080
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: 28127051
pmcid: 5428335