Abstract
Cannabis has been used for various medicinal applications including, but not limited to, cancer: most commonly to treat chemotherapy-associated side effects. Cannabis is often used for its palliative effects in the form of purified cannabinoids, or as extracts. This study was conducted using two breast cancer cell lines and aimed to evaluate potential anti-proliferative “intra-entourage effects” between purified phytocannabinoids resembling the THC and CBD ratios of medicinal and recreational cannabis strains, as well as to investigate potential “inter-entourage effects” between the different ratios and the phytochemicals found in a Cannabis sativa extract. This study also aimed to evaluate the potential interaction between cannabinoids and chemotherapeutic agents. The data identified an intra-entourage effect present in the MCF-7 cells when treated with a recreational, but not a medicinal, cannabis formulation. This effect may be due to THC partially exerting its anti-proliferative effects through the estrogen receptor (ER), present in the MCF-7 cell line. Little to no intra-entourage effects were observed in the MDA-MB-231 cell line and no inter-entourage effects were observed in either cell line. The simultaneous treatment of the MCF-7 cell line with various cannabinoid formulations and the common breast cancer treatment, tamoxifen, resulted in the diminished anti-proliferative activity of tamoxifen, an effect that was more evident when combined with recreational cannabis formulations. Since cannabis is commonly used in palliative care to treat chemotherapy-associated side effects, further research is required to investigate the potential interference of various cannabis formulations to ensure that the efficacy of chemotherapeutic agents is not compromised.
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References
Afrin F, Chi M, Eamens AL, Duchatel RJ, Douglas AM, Schneider J, Gedye C, Woldu AS, Dun MD (2020) Can hemp help? Low-THC cannabis and non-THC cannabinoids for the treatment of cancer. Cancers 12:1033. https://doi.org/10.3390/cancers12041033
Alsherbiny MA, Li CG (2019) Medicinal cannabis—potential drug interactions. Medicines 6:3. https://doi.org/10.3390/medicines6010003
Alsherbiny MA, Bhuyan DJ, Low MN, Chang D, Li CG (2021) Synergistic interactions of cannabidiol with chemotherapeutic drugs in MCF7 cells: mode of interaction and proteomics analysis of mechanisms. Int J Mol Sci 22:10103. https://doi.org/10.3390/ijms221810103
Andre CM, Hausman J-F, Guerriero G (2016) Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci 7:19. https://doi.org/10.3389/fpls.2016.00019
Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee M-H, Vogel Z, Bisogno T, de Petrocellis L, di Marzo V, Mechoulam R (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31. https://doi.org/10.1016/S0014-2999(98)00392-6
Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, Tundidor I, Andradas C, García-Taboada E, Wade J, Smith S, Guzmán M, Pérez-Gómez E (2018) Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol 157:285–293. https://doi.org/10.1016/j.bcp.2018.06.025
Borrelli F, Pagano E, Romano B, Panzera S, Maiello F, Coppola D, de Petrocellis L, Buono L, Orlando P, Izzo AA (2014) Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis 35:2787–2797. https://doi.org/10.1093/carcin/bgu205
Chang M (2012) Tamoxifen resistance in breast cancer. Biomol Therap 20:256. https://doi.org/10.4062/biomolther.2012.20.3.256
Chou T-C (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681. https://doi.org/10.1124/pr.58.3.10
Chou T-C (2010) Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res 70:440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
de Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, di Marzo V (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494. https://doi.org/10.1111/j.1476-5381.2010.01166.x
Elder JJ, Knoderer HM (2015) Characterization of dronabinol usage in a pediatric oncology population. J Pediat Pharmacol Therap 20:462–467. https://doi.org/10.5863/1551-6776-20.6.462
Fallon MT, Albert Lux E, Mcquade R, Rossetti S, Sanchez R, Sun W, Wright S, Lichtman AH, Kornyeyeva E (2017) Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain 11:119–133. https://doi.org/10.1177/2049463717710042
Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D’Ilio S, Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S (2014) Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS ONE 9:e88193. https://doi.org/10.1371/journal.pone.0088193
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386. https://doi.org/10.1002/ijc.29210
Ferro R, Adamska A, Lattanzio R, Mavrommati I, Edling CE, Arifin SA, Fyffe CA, Sala G, Sacchetto L, Chiorino G, de Laurenzi V, Piantelli M, Sansom OJ, Maffucci T, Falasca M (2018) GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene 37:6368–6382. https://doi.org/10.1038/s41388-018-0390-1
Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, Rogers MJ, Rajnicek AM, Ross RA (2010) A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol 160:762–771. https://doi.org/10.1111/j.1476-5381.2010.00743.x
Fraguas-Sánchez AI, Fernández-Carballido A, Simancas-Herbada R, Martin-Sabroso C, Torres-Suárez AI (2020) CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer. Int J Pharm 574:118916. https://doi.org/10.1016/j.ijpharm.2019.118916
Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, Novotny PJ, Christensen B (2002) Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 20:567–573. https://doi.org/10.1200/jco.2002.20.2.567
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT (2010) Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symp Manag 39:167–179. https://doi.org/10.1016/j.jpainsymman.2009.06.008
Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (2013) An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage 46:207–218. https://doi.org/10.1016/j.jpainsymman.2012.07.014
Jorfi S, Ansa-Addo EA, Kholia S, Stratton D, Valley S, Lange S, Inal J (2015) Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo. Sci Rep 5:13006. https://doi.org/10.1038/srep13006
Jose A, Thomas L, Baburaj G, Munisamy M, Rao M (2020) Cannabinoids as an alternative option for conventional analgesics in cancer pain management: a pharmacogenomics perspective. Indian J Palliat Care 26:129–133. https://doi.org/10.4103/ijpc.ijpc_155_19
Kisková T, Mungenast F, Suváková M, Jäger W, Thalhammer T (2019) Future aspects for cannabinoids in breast cancer therapy. Int J Mol Sci 20:1673. https://doi.org/10.3390/ijms20071673
Koch R, Aung T, Vogel D, Chapuy B, Wenzel D, Becker S, Sinzig U, Venkataramani V, von Mach T, Jacob R, Truemper L, Wulf GG (2016) Nuclear trapping through inhibition of exosomal export by indomethacin increases cytostatic efficacy of doxorubicin and pixantrone. Clin Cancer Res 22:395–404. https://doi.org/10.1158/1078-0432.ccr-15-0577
Kosgodage US, Trindade RP, Thompson PR, Inal JM, Lange S (2017) Chloramidine/bisindolylmaleimide-I-mediated inhibition of exosome and microvesicle release and enhanced efficacy of cancer chemotherapy. Int J Mol Sci. https://doi.org/10.3390/ijms18051007
Kosgodage US, Mould R, Henley AB, Nunn AV, Guy GW, Thomas EL, Inal JM, Bell JD, Lange S (2018) Cannabidiol (CBD) is a novel inhibitor for exosome and microvesicle (EMV) release in cancer. Front Pharmacol 9:889–889. https://doi.org/10.3389/fphar.2018.00889
Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT (2018) Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symp Manage 55:179-188.e1. https://doi.org/10.1016/j.jpainsymman.2017.09.001
Liu J, Chen Y, Shuai S, Ding D, Li R, Luo R (2014) TRPM8 promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3β pathway. Tumor Biol 35:8969–8977. https://doi.org/10.1007/s13277-014-2077-8
Liu Z, Wu H, Wei Z, Wang X, Shen P, Wang S, Wang A, Chen W, Lu Y (2016) TRPM8: a potential target for cancer treatment. J Cancer Res Clin Oncol 142:1871–1881. https://doi.org/10.1007/s00432-015-2112-1
Lynch ME, Cesar-Rittenberg P, Hohmann AG (2014) A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47:166–173. https://doi.org/10.1016/j.jpainsymman.2013.02.018
Mangal N, Erridge S, Habib N, Sadanandam A, Reebye V, Sodergren MH (2021) Cannabinoids in the landscape of cancer. J Cancer Res Clin Oncol 147:2507–2534. https://doi.org/10.1007/s00432-021-03710-7
Martell K, Fairchild A, Legerrier B, Sinha R, Baker S, Liu H, Ghose A, Olivotto I, Kerba M (2018) Rates of cannabis use in patients with cancer. Curr Oncol 25:219–225. https://doi.org/10.3747/co.25.3983
Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D (2004) Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 308:838–845. https://doi.org/10.1124/jpet.103.061002
May MB, Glode AE (2016) Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Manag Res 8:49. https://doi.org/10.2147/CMAR.S81425
Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, Baranowski V (2007) Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin 23:533–543. https://doi.org/10.1185/030079907x167525
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4
Mouhamed Y, Vishnyakov A, Qorri B, Sambi M, Frank SS, Nowierski C, Lamba A, Bhatti U, Szewczuk MR (2018) Therapeutic potential of medicinal marijuana: an educational primer for health care professionals. Drug Healthc Patient Saf 10:45. https://doi.org/10.2147/DHPS.S158592
Munson A, Harris L, Friedman M, Dewey W, Carchman R (1975) Antineoplastic activity of cannabinoids. J Natl Cancer Inst 55:597–602. https://doi.org/10.1093/jnci/55.3.597
Muralidharan-Chari V, Kohan HG, Asimakopoulos AG, Sudha T, Sell S, Kannan K, Boroujerdi M, Davis PJ, Mousa SA (2016) Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells. Oncotarget 7:50365–50379. https://doi.org/10.18632/oncotarget.10395
Nabissi M, Morelli MB, Santoni M, Santoni G (2012) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34:48–57. https://doi.org/10.1093/carcin/bgs328
Namdar D, Voet H, Ajjampura V, Nadarajan S, Mayzlish-Gati E, Mazuz M, Shalev N, Koltai H (2019) Terpenoids and phytocannabinoids co-produced in Cannabis sativa strains show specific interaction for cell cytotoxic activity. Molecules 24:3031. https://doi.org/10.3390/molecules24173031
Parker LA, Rock EM, Limebeer CL (2011) Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol 163:1411–1422. https://doi.org/10.1111/j.1476-5381.2010.01176.x
Pergam SA, Woodfield MC, Lee CM, Cheng G-S, Baker KK, Marquis SR, Fann JR (2017) Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer 123:4488–4497. https://doi.org/10.1002/cncr.30879
Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT (2012) Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13:438–449. https://doi.org/10.1016/j.jpain.2012.01.003
Ramlugon S, Levendal RA, Frost C (2018) Time-dependent effect of phytocannabinoid treatments in fat cells. Phytother Res 32:1080–1089. https://doi.org/10.1002/ptr.6047
Repka MA, Munjal M, Elsohly MA, Ross SA (2006) Temperature stability and bioadhesive properties of Δ9-tetrahydrocannabinol incorporated hydroxypropylcellulose polymer matrix systems. Drug Dev Ind Pharm 32:21–32. https://doi.org/10.1080/03639040500387914
Russo EB (2011) Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163:1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
Russo EB (2019) The case for the entourage effect and conventional breeding of clinical cannabis: no “strain”, no gain. Front Plant Sci 9:1969. https://doi.org/10.3389/fpls.2018.01969
Saadeh CE, Rustem DR (2018) Medical marijuana use in a community cancer center. J Oncol Pract 14:e566–e578. https://doi.org/10.1200/JOP.18.00057
Santiago M, Sachdev S, Arnold JC, McGregor IS, Connor M (2019) Absence of entourage: terpenoids commonly found in cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1 and CB2 receptors. Cannab Cannabin Res 4:165–176. https://doi.org/10.1089/can.2019.0016
Schoeman R, Beukes N, Frost C (2020) Cannabinoid combination induces cytoplasmic vacuolation in mcf-7 breast cancer cells. Molecules 25:4682. https://doi.org/10.3390/molecules25204682
Small E, Beckstead H (1973) Cannabinoid phenotypes in Cannabis sativa. Nature 245:147–148. https://doi.org/10.1038/245147a0
Steele G, Arneson T, Zylla D (2019) A comprehensive review of cannabis in patients with cancer: availability in the USA, general efficacy, and safety. Curr Oncol Rep 21:10. https://doi.org/10.1007/s11912-019-0757-7
Stuyt E (2018) The problem with the current high potency THC marijuana from the perspective of an addiction psychiatrist. Missour Med 115:482
Takeda S, Yoshida K, Nishimura H, Harada M, Okajima S, Miyoshi H, Okamoto Y, Amamoto T, Watanabe K, Omiecinski CJ (2013) Δ9-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ). Chem Res Toxicol 26:1073–1079. https://doi.org/10.1021/tx4000446
Tao JJ, Visvanathan K, Wolff AC (2015) Long term side effects of adjuvant chemotherapy in patients with early breast cancer. The Breast 24:S149–S153. https://doi.org/10.1016/j.breast.2015.07.035
von Bueren A, Schlumpf M, Lichtensteiger W (2008) Delta (9)-tetrahydrocannabinol inhibits 17β-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells. Anticancer Res 28:85–89
Walsh D, Kirkova J, Davis MP (2005) The efficacy and tolerability of long-term use of dronabinol in cancer-related anorexia: a case series. J Pain Symp Manag 30:493–495. https://doi.org/10.1016/j.jpainsymman.2005.11.007
Ware MA, Daeninck P, Maida V (2008) A review of nabilone in the treatment of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manag 4:99. https://doi.org/10.2147/TCRM.S1132
Wasik A, Almestrand S, Wang X, Hultenby K, Dackland Å-L, Andersson P, Kimby E, Christensson B, Sander B (2011) WIN55, 212–2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells. Cell Death Dis 2:e225–e225. https://doi.org/10.1038/cddis.2011.106
Zhou X, Seto SW, Chang D, Kiat H, Razmovski-Naumovski V, Chan K, Bensoussan A (2016) Synergistic effects of Chinese herbal medicine: a comprehensive review of methodology and current research. Front Pharmacol. https://doi.org/10.3389/fphar.2016.00201
Zutt M, Hänssle H, Emmert S, Neumann C, Kretschmer L (2006) Dronabinol for supportive therapy in patients with malignant melanoma and liver metastases. Hautarzt 57:423–427. https://doi.org/10.1007/s00105-005-1063-x
Acknowledgements
We would like to thank the South African community for contacting our research group and inspiring this investigation when they discovered our research interests. We hope our limited findings will assist them in making informed health decisions. R. Schoeman and A. de la Harpe would like to acknowledge Nelson Mandela University and the National Research Foundation (NRF) for the provision of research scholarships. Running costs for this study were covered by the Nelson Mandela University (NMU).
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The funding has been received from National Research Foundation.
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RS: conceptualization; methodology; formal analysis; investigation. ADLH: writing—original draft, visualization. NB: methodology; supervision; writing—review and editing. CLF: conceptualization; methodology; supervision; writing—review and editing; resources; project administration; funding acquisition.
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Schoeman, R., de la Harpe, A., Beukes, N. et al. Cannabis with breast cancer treatment: propitious or pernicious?. 3 Biotech 12, 54 (2022). https://doi.org/10.1007/s13205-021-03102-1
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DOI: https://doi.org/10.1007/s13205-021-03102-1