Recently, cannabinoids, the active components of marijuana and their endogenous counterparts, have been shown to inhibit the growth of malignant tumors both in vitro and in vivo. On the other hand, the treatment of cancer cells with nanomolar concentrations of cannabinoids lead to accelerated cell proliferation. Orally applicable delta 9-tetrahydrocannabinol and its synthetic derivative have been approved by the United States Food and Drug Administration to be used as the antiemetic drugs during chemotherapy for cancer patients. However, it hasn’t been well known how cannabinoids modulate the effects of chemotherapeutic agents to malignant tumors.

In this study, we investigated how the endogenous cannabinoid anandamide (AEA) modulates the effect of paclitaxel to gastric cancer cell lines. In NUGC-3, 10μM AEA enhanced the effect of paclitaxel time-dependently and depending on the dose of paclitaxel. After 4 days treatment of 10μM paclitaxel, cell viability was reduced to 37.5% of control. Cell viability was further reduced to 7.1% after treatment of 10μM paclitaxel with 10μM AEA. The same effect was observed in HGC-27, AZ-521 and MKN-1. On the other hand, at nanomolar concentrations AEA did not change the cytotoxic effects of paclitaxel in those cell lines.

Double-stained with Annexin V-FITC and Propidium Iodide, 10μM AEA treatment of NUGC-3 and HGC-27 increased the population of annexinV (+) apoptotic cells, and enhanced paclitaxel-induced apoptosis. On the other hand, at nanomolar concentrations, AEA didn’t change the apoptosis induced by paclitaxel in NUGC-3. In cell cycle analysis 10μM AEA decreased G2/M arrest induced by paclitaxel and enhanced the increase of sub-G1 phase in NUGC-3 and HGC-27.

Our study indicates that AEA and paclitaxel could be a good combination in the treatment of gastric cancer and that medication of cannabinoids can be appropriately used in the treatment by paclitaxel.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA