Orally applicable Δ9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic
drugs during chemotherapy in cancer patients. However, it is not well known how cannabinoids
influence the effects of chemotherapeutic agents on malignant tumors. In this study,
we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect
of paclitaxel on gastric cancer cell lines. In the human gastric cancer cell line,
HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at
concentrations under 1 μM, while it strongly suppressed proliferation through the
induction of apoptosis at 10 μM. This bimodal effect was reproduced by a selective
CB1 agonist, arachidonyl-2-chloroethylamide, although the effects were less marked.
When AEA was used with paclitaxel, AEA at 10 μM synergistically enhanced the cytotoxic
effect of paclitaxel, whereas it showed no significant effect at lower concentrations.
Flow cytometric analysis revealed that addition of 10 μM AEA synergistically enhanced
paclitaxel-induced apoptosis, possibly through the activation of caspase-3, -8, and
-9. Our results suggest that cannabinoids could be a good palliative agent for cancer
patients receiving paclitaxel.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Surgical ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cannabinoid receptor ligands: Clinical and neuropharmacological considerations, relevant to future drug discovery and development.Exp Opin Invest Drugs. 2000; 9: 1
- The endocannabinoid system as a target for therapeutic drugs.Trends Pharmacol Sci. 2000; 21: 218
- The endocannabinoid nervous system: Unique opportunities for therapeutic intervention.Pharmacol Ther. 2001; 90: 45
- Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992; 258: 1946
- Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.Biochem Pharmacol. 1995; 50: 83
- Structure of a cannabinoid receptor and functional expression of the cloned cDNA.Nature. 1999; 346: 561
- Differential expression of cannabinoid receptors in the human colon: Cannabinoids promote epithelial wound healing.Gastroenterology. 2005; 129: 437
- Possible endocannabinoid control of colorectal cancer growth.Gastroenterology. 2003; 125: 677
- Molecular characterization of a peripheral receptor for cannabinoids.Nature. 1993; 365: 61
- Cannabinoid-based drugs as anti-inflammatory therapeutics.Nat Rev Immunol. 2005; 5: 400
- Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.Nature. 2005; 434: 782
- Cannabinoids: Potential anticancer agents.Nat Rev Cancer. 2003; 3: 745
- Antitumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation.Nat Med. 2000; 6: 313
- The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation.Proc Natl Acad Sci USA. 1998; 95: 8375
- Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation.Endocrinology. 2000; 141: 118
- Cannabinoid receptor as a novel target for the treatment of prostate cancer.Cancer Res. 2005; 65: 1635
- Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: Implication of epidermal growth factor receptor down-regulation and ceramide production.Prostate. 2003; 56: 1
- Cannabinoids and cell fate.Pharmacol Ther. 2002; 5: 175
- Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.J Clin Invest. 2003; 111: 43
- Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas.Cancer Res. 2004; 64: 5617
- Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: Actions on signals involved in angiogenesis and metastasis.FASEB J. 2003; 17: 1771
- Cannabinoids induce cancer cell proliferation via tumor necrosis factor α-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor.Cancer Res. 2004; 64: 1943
- Established and potential therapeutic applications of cannabinoids in oncology.Support Care Cancer. 2003; 11: 137
- Medical marijuana initiatives: Are they justified? How successful are they likely to be?.Cent Nerv Syst Drugs. 2003; 17: 689
- A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats.Pain. 2005; 118: 23
- Paclitaxel-induced apoptosis in human gastric carcinoma cell lines.Cancer. 1996; 77: 14
- Phase II study of Taxol in patients with untreated metastatic gastric carcinoma.Cancer J Sci Am. 1998; 4: 269
- Phase II trial of paclitaxel by 3-h infusion for advanced gastric cancer with short premedication for prophylaxis against paclitaxel-associated hypersensitivity reactions.Ann Oncol. 2001; 12: 1133
- Phase II trial of outpatient schedule of paclitaxel in patients with previously untreated metastatic, measurable adenocarcinoma of the stomach.Jpn J Clin Oncol. 2001; 31: 275
- An early Phase II study of a 3-h infusion of paclitaxel for advanced gastric cancer.Am J Clin Oncol. 1998; 21: 416
- Paclitaxel (taxol).N. Engl. J. Med. 1995; 332: 1004
- Microtubules as a target for anticancer drugs.Nat Rev Cancer. 2004; 4: 253
- Microtubule-targeted anticancer agents and apoptosis.Oncogene. 2003; 22: 9075
- Inhibition of the mammalian target of rapamycin (mTor) by rapamycin increases chemosensitivity of CaSki cells to paclitaxel.Eur J Cancer. 2006; 42: 934
- Differential sensitivity of paclitaxel-induced apoptosis in human esophageal squamous cell carcinoma cell lines.Cancer Chemother Pharmacol. 2006; 57: 301
- Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability.Biochem Pharmacol. 2000; 60: 1807
- The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.Biochem Pharmacol. 2006; 71: 1146
- Taxol-induced ceramide generation and apoptosis in human breast cancer cells.Cancer Chemother Pharmacol. 2001; 47: 444
- The effect of orally and rectally administered δ9-tetrahydrocannabinol on spasticity: A pilot study with two patients.Int J Clin Pharmacol Ther. 1996; 34: 446
- Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans.Pharmacol Biochem Behav. 1991; 40: 517
Article info
Publication history
Published online: August 11, 2008
Received:
March 9,
2008
Identification
Copyright
© 2009 Published by Elsevier Inc. All rights reserved.
