Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines.
Orally applicable Delta9-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 microM, while it strongly suppressed proliferation through the induction of apoptosis at 10 microM. 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 microM synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. Flow cytometric analysis revealed that addition of 10 microM 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.
Miyato
Hideyo
H
Department of Surgery, Division of Surgical Oncology, University of Tokyo, Tokyo, Japan. hmiya-tky@umin.ac.jp
Kitayama
Joji
J
Yamashita
Hiroharu
H
Souma
Daisuke
D
Asakage
Masahiro
M
Yamada
Jun
J
Nagawa
Hirokazu
H
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D063388:Endocannabinoids; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy*
D000972:Antineoplastic Agents, Phytogenic; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D020169:Caspases; D017239:Paclitaxel; C078814:anandamide