In Vitro Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

Download Download as PDF (Size:1856KB)  HTML   XML  PP. 806-820  
DOI: 10.4236/pp.2014.58091    3,318 Downloads   8,078 Views   Citations

ABSTRACT

Cannabinoids, the active components of Cannabis sativa Linnaeus, have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression, but their use in chemotherapy is limited by their psychotropic activity. To date, cannabinoids have been successfully used in the treatment of nausea and vomiting, two common side effects that accompany chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g. cannabidiol and cannabigerol, seem to be devoid of psychotropic properties. However, the precise pathways through which these molecules produce an antitumor effect have not yet been fully characterized. We therefore investigated the antitumor and anti-inflammatory activities of cannabidiol (CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed whether there is any advantage in using cannabis extracts enriched in cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell lines clearly indicate that cannabidiol is a potent inhibitor of cancer cell growth, with significantly lower potency in non-cancer cells. The mRNA expression level of cannabinoid receptors CB1 and CB2, vascular endothelial growth factor (VEGF), PSA (prostate specific antigen) are significantly higher in human prostate cell lines. Treatment with Cannabis extract containing high CBD down regulates CB1, CB2, VEGF, PSA, pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support the concept that cannabidiol, which lacks psychotropic activity, may possess anti-inflammatory property and down regulates both cannabinoid receptors, PSA, VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen responsive LNCaP cells and may effectively inhibit spheroid formation in cancer stem cells. This activity may contribute to its anticancer and chemosensitizing effect against prostate cancer. Cannabidiol and other non-habit forming cannabinoids could be used as novel therapeutic agents for the treatment of prostate cancer.

Cite this paper

Sharma, M. , Hudson, J. , Adomat, H. , Guns, E. and Cox, M. (2014) In Vitro Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines. Pharmacology & Pharmacy, 5, 806-820. doi: 10.4236/pp.2014.58091.

References

[1] Gnanapragasam, V.J., Robinson, M.C., Marsh, C., Robson, C.N., Hamdy, F.C. and Leung, H.Y. (2003) FGF8 Isoform b Expression in Human Prostate Cancer. British Journal of Cancer, 88, 1432-1438.
http://dx.doi.org/10.1038/sj.bjc.6600875
[2] Lara Jr., P.N., Twardowski, P. and Quinn, D.I. (2004) Angiogenesistargeted Therapies in Prostate Cancer. Clinical Prostate Cancer, 3, 165-173.
http://dx.doi.org/10.3816/CGC.2004.n.027
[3] Petrylak, D.P., Tangen, C.M., Hussain, M.H., Lara Jr., P.N., Jones, J.A., Taplin, M.E., Burch, P.A., Berry, D., Moinpour, C., Kohli, M., Benson, M.C., Small, E.J., et al. (2004) Docetaxel and Estramustine Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer. The New England Journal of Medicine, 351, 1513-1520.
[4] Maitland, N.J. and Collins, A.T. (2008) Prostate Cancer Stem Cells: A New Target for Therapy. Journal of Clinical Oncology, 26, 2862-2870.
http://dx.doi.org/10.1200/JCO.2007.15.1472
[5] Holtz, M., Forman, S.J. and Bhatia, R. (2007) Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment. The Journal of Cancer Research, 67, 1113-1120.
http://dx.doi.org/10.1158/0008-5472.CAN-06-2014
[6] Lawson, D.A., Zong, Y., Memarzadeh, S., Xin, L., Huang, J. and Witte, O.N. (2010) Basal Epithelial Stem Cells Are Efficient Targets for Prostate Cancer Initiation. Proceedings of the National Academy of Sciences of the United States of America, 107, 2610-2615.
http://dx.doi.org/10.1073/pnas.0913873107
[7] Guzman, M. (2003) Cannabinoids: Potential Anticancer Agents. Nature Reviews Cancer, 3, 745-755.
http://dx.doi.org/10.1038/nrc1188
[8] Velasco, G., Galve-Roperh, I., Sanchez, C., Blazquez, C. and Guzman, M. (2004) Hypothesis: Cannabinoid Therapy for the Treatment of Gliomas. Neuropharmacology, 47, 315-323.
http://dx.doi.org/10.1016/j.neuropharm.2004.04.016
[9] Sarkar, K.P., Obara, S., Nakata, M., Kitajima, I. and Maruyama, I. (2000) Anandamide Induces Apoptosis of PC-12 Cells: Involvement of Superoxide and Caspase-3. FEBS Letters, 472, 1039-1044.
[10] Maccarrone, M., Lorenzon, T., Bari, M., Melino, G. and Finazzi-Agro, A. (2000) Anandamide Induces Apoptosis in Human Cells via Vanilloid Receptors. Evidence for a Protective Role of Cannabinoid Receptors. The Journal of Biological Chemistry, 275, 31938-31945.
http://dx.doi.org/10.1074/jbc.M005722200
[11] Chan, G.C., Hinds, T.R., Impey, S. and Storm, D.R. (1998) Hippocampal Neurotoxicity of D9 Tetrahydrocannabinol. The Journal of Neuroscience, 18, 5322-5332.
[12] Guzman, M., Sanchez, C. and Galve-Roperh, I. (2001) Control of the Cell Survival/Death Decision by Cannabinoids. Journal of Molecular Medicine, 78, 613-625.
http://dx.doi.org/10.1007/s001090000177
[13] De Petrocellis, L., Ligresti, A., SchianoMoriello, A., Iappelli, M., Verde, R., Stott, C.G., Cristino, L., Orlando, P. and Di Marzo, V. (2013) Non-THC Cannabinoids Inhibit Prostate Carcinoma Growth in Vitro and in Vivo: Pro-Apoptotic Effects and Underlying Mechanisms. British Journal of Pharmacology, 168, 79-102.
http://dx.doi.org/10.1111/j.1476-5381.2012.02027.x
[14] Sreevalsan, S., Joseph, S., Jutooru, I., Chadalapaka, G. and Safe, S.H. (2011) Induction of Apoptosis by Cannabinoids in Prostate and Colon Cancer Cells Is Phosphatase Dependent. Anticancer Research, 31, 3799-3807.
[15] Hornby, A.P. and Sharma, M. (2010) Standardized Cannabis in Multiple Sclerosis: A Case Report. Cases Journal, 3, 1-5.
[16] Hornby, A.P., Sharma, M. and Stegman, B. (2009) Standardized Natural Product Cannabis in Pain Management and Observations at a Canadian Compassion Society: A Case Report. Cases Journal, 2, 1-3.
[17] Sharma, M. (2012) Cannabis Responsive Head Injury Induced Multiple Disabilities: A Case Report. Pharmacology & Pharmacy, 3, 58-61.
[18] Robson, P. (2005) Human Studies of Cannabinoids and Medicinal Cannabis. Handbook of Experimental Pharmacology, 168, 719-756.
[19] Kogan, N.M. (2005) Cannabinoids and Cancer. Mini-Reviews in Medicinal Chemistry, 5, 941-952.
http://dx.doi.org/10.2174/138955705774329555
[20] Melck, D., De Petrocellis, L., Orlando, P., Bisogno, T., Laezza, C., Bifulco, M. and Di Marzo, V. (2000) Suppression of Nerve Growth Factor Trk Receptors and Prolactin Receptors by Endocannabinoids Leads to Inhibition of Human Breast and Prostate Cancer Cell Proliferation. Endocrinology, 141, 118-126.
[21] Casanova, M.L., Blázquez, C., Martínez-Palacio, J., Villanueva, C., Fernández-Aceñero, M.J., Huffman, J.W., Jorcano, J.L. and Guzmán, M. (2003) Inhibition of Skin Tumor Growth and Angiogenesis in Vivo by Activation of Cannabinoid Receptors. The Journal of Clinical Investigation, 111, 43-50.
http://dx.doi.org/10.1172/JCI200316116
[22] McKallip, R.J., Nagarkatti, M. and Nagarkatti, P.S. (2005) Delta-9-Tetrahydrocannabinol Enhances Breast Cancer Growth and Metastasis by Suppression of the Antitumor Immune Response. The Journal of Immunology, 174, 3281-3289.
http://dx.doi.org/10.4049/jimmunol.174.6.3281
[23] Pertwee, R.G. (1997) Pharmacology of Cannabinoid CB1 and CB2 Receptors. Pharmacology & Therapeutics, 74, 129-180.
http://dx.doi.org/10.1016/S0163-7258(97)82001-3
[24] Walsh, D., Nelson, K.A. and Mahmoud, F.A. (2003) Established and Potential Therapeutic Applications of Cannabinoids in Oncology. Support Care Cancer, 11,137-143.
[25] Mechoulam, R., Parker, L.A. and Gallily, R. (2002) Cannabidiol: An Overview of Some Pharmacological Aspects. The Journal of Clinical Pharmacology, 42, 11S-19S.
http://dx.doi.org/10.1002/j.1552-4604.2002.tb05998.x
[26] Pertwee, R.G. (2004) The Pharmacology and Therapeutic Potential of Cannabidiol. In: Di Marzo, V., Ed., Cannabinoids, Kluwer Academic/Plenum Publishers, New York, 32-83.
[27] Russo, E. and Guy, G.W. (2006) A Tale of Two Cannabinoids: The Therapeutic Rationale for Combining Tetrahydrocannabinol and Cannabidiol. Medical Hypotheses, 66, 234-246.
http://dx.doi.org/10.1016/j.mehy.2005.08.026
[28] Ilan, A.B., Gevins, A., Coleman, M., ElSohly, M.A. and de Wit, H. (2005) Neurophysiological and Subjective Profile of Marijuana with Varying Concentrations of Cannabinoids. Behavioural Pharmacology, 16, 487-496.
http://dx.doi.org/10.1097/00008877-200509000-00023
[29] Colasanti, B.K. (1990) A Comparison of the Ocular and Central Effects of Delta 9-Tetrahydrocannabinol and Cannabigerol. Journal of Ocular Pharmacology and Therapeutics, l6, 259-269.
http://dx.doi.org/10.1089/jop.1990.6.259
[30] Schmittgen, T.D. and Livak, K.J. (2008) Analyzing Real-Time PCR Data by the Comparative CT Method. Nature Protocols, 3, 1101-1108.
http://dx.doi.org/10.1038/nprot.2008.73
[31] Naz, R.K. and Herness, E.A. (2001) Prostate-Specific Genes: Present Status and Future Direction. Frontiers in Bioscience, 6, 1083-1088.
[32] Stamey, T.A., Yang, N., Hay, A.R., McNeal, J.E., Freiha, F.S. and Redwine, E. (1987) Prostate-Specific Antigen as a Serum Marker for Adenocarcinoma of the Prostate. The New England Journal of Medicine, 317, 909-916.
http://dx.doi.org/10.1056/NEJM198710083171501
[33] Joseph, I.B., Nelson, J.B., Denmeade, S.R. and Isaacs, J.T. (1997) Androgens Regulate Vascular Endothelial Growth Factor Content in Normal and Malignant Prostatic Tissue. Clinical Cancer Research, 12, 2507-2511.
[34] Reynolds, B.A. and Weiss, S. (1992) Generation of Neurons and Astrocytes from Isolated Cells of the Adult Mammalian Central Nervous System. Science, 255, 1707-1710.
http://dx.doi.org/10.1126/science.1553558
[35] Amanatullah, D.F., Reutens, A.T., Zafonte, B.T., Fu, M., Mani, S. and Pestell, R.G. (2000) Cell-Cycle Dysregulation and the Molecular Mechanisms of Prostate Cancer. Frontiers in Bioscience, 5, D372-D390.
[36] Koivisto, P., Kolmer, M., Visakorpi, T. and Kallioniemi, O.P. (1998) Androgen Receptor Gene and Hormonal Therapy Failure of Prostate Cancer. American Journal of Pathology, 152, 1-9.
[37] Balk, S.P., Ko, Y.J. and Bubley, G.J. (2003) Biology of Prostate-Specific Antigen. Journal of Clinical Oncology, 21, 383-391.
http://dx.doi.org/10.1200/JCO.2003.02.083
[38] Montgomery, B.T., Young, C.Y., Bilhartz, D.L., Andrews, P.E., Prescott, J.L., Thompson, N.F., Prescott, J.L. and Tindall, D.J. (1992) Hormonal Regulation of Prostate-Specific Antigen (PSA) Glycoprotein in the Human Prostatic Adenocarcinoma Cell Line, LNCaP. The Prostate, 21, 63-73.
http://dx.doi.org/10.1002/pros.2990210107
[39] Lee, C., Sutkowski, D.M., Sensibar, J.A., Zelner, D., Kim, I., Amsel, I., et al. (1995) Regulation of Proliferation and Production of Prostate-Specific Antigen in Androgen-Sensitive Prostatic Cancer Cells, LNCaP, by Dihydrotestosterone. Endocrinology, 136, 796-803.
[40] Mazzucchelli, R., Montironi, R., Santinelli, A., Lucarini, G., Pugnaloni, A. and Biagini, G. (2000) Vascular Endothelial Growth Factor Expression and Capillary Architecture in High Grade PIN and Prostate Cancer in Untreated and Androgen-Ablated Patients. The Prostate, 45, 72-79.
[41] Blázquez, C., Casanova, M.L., Planas, A., Del Pulgar, T.G., Villanueva, C., Fernández-Aceñero, M.J., et al. (2003) Inhibition of Tumor Angiogenesis by Cannabinoids. The FASEB Journal, 17, 529-531.
[42] Mantovani, A. (2007) Cancer: An Infernal Triangle. Nature, 436, 547-548.
http://dx.doi.org/10.1038/448547a
[43] van der Poel, H.G. (2007) Molecular Markers in the Diagnosis of Prostate Cancer. Critical Reviews in Oncology/Hematology, 61, 104-139.
http://dx.doi.org/10.1016/j.critrevonc.2006.07.003
[44] Dubrovska, A., Kim, S., Salamone, R.J., Walker, J.R., Maira, S.M., Garcia-Echeverria, C., Schultz, P.G. and Reddy, V.A. (2009) The Role of PTEN/Akt/PI3K Signaling in the Maintenance and Viability of Prostate Cancer Stem-Like Cell Populations. Proceedings of the National Academy of Sciences of the United States of America, 106, 268-273.
http://dx.doi.org/10.1073/pnas.0810956106
[45] Magni, P., Ruscica, M., Dozio, E., Rizzi, E., Beretta, G. and Facino, R.M. (2012) Parthenolide Inhibits the LPS-Induced Secretion of IL-6 and TNF-α and NF-κB Nuclear Translocation in BV-2 Microglia. Phytotherapy Research, 26, 1405-1409.
http://dx.doi.org/10.1002/ptr.3732
[46] Yan, Y.Y., Wang, Y.W., Chen, S.L., Zhuang, S.R. and Wang, C.K. (2013) Anti-Inflammatory Effects of Phenolic Crude Extracts from Five Fractions of Corchorus olitorius L. Food Chemistry, 138, 1008-1014.
http://dx.doi.org/10.1016/j.foodchem.2012.10.052

  
comments powered by Disqus

Sponsors, Associates, and Links >>

  • ADVERTISEMENT

Copyright © 2016 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.