The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation

Abstract

In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immuno-regulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic.

Figure 1

Cannabis/Cannabinoids Administration to Syngeneic Bone Marrow Transplantation Model. A: Recipient C57BL/6 mice (R) received lethal whole-body irradiation and were reconstituted with 8×10⁶ donor C57BL/6 (D) bone marrow cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. Blood samples for complete blood counts were obtained once a week. B: Lymphocyte counts (day 21 after transplantation) in pure cannabinoid-treated groups (left) and BDS-treated groups (right) are presented. C: Platelet counts in pure cannabinoid-treated groups (left) and BDS-treated groups (right), day 14 after transplantation. * P<0.05; ** P<0.001; *** P<0.0001. Modified from Figure 4 in Khuja et al.; reused under creative commons license (CC BY 4.0). BDS, botanical drug substance; BMT, bone marrow transplantation; IP, intraperitoneally; THC, Δ9-tetrahydrocannabinol.

Figure 2

The Role of CB2 in Lymphocyte Recovery. A: Syngeneic BMT from CB2 KO donor mice to C57BL/6 WT mice. Average lymphocyte counts at different time points (left) and counts on day 21 after transplantation (right). *** P<0.0001. B: Syngeneic BMT from C57BL/6 WT donor mice to CB2 KO mice. Average lymphocyte counts at different time points (left) and counts on day 21 after transplantation (right). C: Model: CB2 has an inhibitory effect on post-transplant rehabilitation of blood lymphocytes. The WT graft rehabilitation will be delayed by endo- (ECS) and/or phyto-cannabinoid (THC) signaling (red T-bars) through CB2. Since the knockout graft does not express CB2, this inhibition is removed. Modified from Figure 5 in Khuja et al.; reused under creative commons license (CC BY 4.0). BMT, bone marrow transplantation; ECS, endocannabinoids; CB2 KO, CB2 knockout; THC, Δ9-tetrahydrocannabinol; WT, wild type.

Figure 3

Cannabis/Cannabinoids Administration for Graft versus Host Disease (GVHD) Prophylaxis. A: Recipient BALB/c mice (R) received lethal whole-body irradiation and were reconstituted with 8×10⁶ donor C57BL/6 (D) bone marrow cells and 2×10⁶ spleen cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. The clinical condition of the mice was evaluated for up to 67 days after transplantation. B: Survival curve THC and CBD, pure cannabinoids treated groups; THC BDS and CBD BDS, cannabis extracts treated groups. C: Average GVHD score THC and CBD, pure cannabinoids treated groups; THC BDS and CBD BDS, cannabis extracts treated groups. Modified from Figure 6 in Khuja et al.; reused under creative commons license (CC BY 4.0). BDS, botanical drug substance; CBD, cannabidiol; IP, intraperitoneally; TCH, Δ9-tetrahydrocannabinol.